A Smart Approach to Treating Tobacco Use Disorder in Persons Living With HIV
Phase: PHASE4
Conditions: Tobacco Use Cessation
Sponsor: Yale University

09262025 
 
Title: A SMART Approach to TreaƟng Tobacco Use Disorder in Persons Living with HIV 
Last Mount Sinai IRB Approval Date: 10/22/2024 
Mount Sinai IRB #: STUDY-19-01121 
NCT #: NCT04490057 
 
 
IRB Protocol and  
StaƟsƟcal Analysis Plan (p. 22, sec. 9.4) 
 

A SMART APPROACH TO TREATING TOBACCO USE 
DISORDER IN PERSONS LIVING WITH HIV 
Protocol Number: STUDY-19-01121 
National Clinical Trial (NCT) Identified Number:  1R01CA243910-01 
Principal Investigator: Keith M Sigel MD, PhD 
<IND/IDE> Sponsor: N/A 
Funded by: NCI 
Version Number:  v.4.0 
 
December 12, 2022 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
1.1, 2.1, 2.2, 
3, 9.1 
Change in primary and secondary outcome 
measures 
At the suggestion of the DSMB 
9.1, 9.2, 9.3, 
9.4 
Change in statistical analysis due to changes in 
outcome measures and new reference added 
At the suggestion of the DSMB and 
biostatistician 
n/a 
Extension of timeline to recruit into Year 5 
To maximize recruitment, which was slowed 
during COVID-19 surges. (Original 
recruitment timeline was through Year 4.) 
5.5 
Addition of script for public service 
announcement to be shown in waiting room 
(SUNY Downstate site only) 
To reach patients in the waiting room so 
that they are aware of the study and can 
refer themselves for screening 
6.3 
Sample size description to be deleted 
Biostatistician discovered that it is in the 
wrong section 
n/a 
Changes made to the MyChart script and 
recruitment letter (Yale site only) 
Requested by the Yale IRB 

 
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
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n/a 
Letter to be sent to enrolled study participants 
who cannot be reached  
Some participants can no longer be reached 
by telephone due to numbers no longer in 
service 
4.1, 7.3 
More specific language about texting 
participants in the study   
Requested by Mount Sinai IRB texting will no 
longer be done on Google Voice as it’s not 
HIPAA compliant and will now be using 
Zoom Phone 

  
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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 2 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 3 
2 
INTRODUCTION ............................................................................................................................................ 4 
2.1 
Study Rationale .................................................................................................................................... 4 
2.2 
Background ........................................................................................................................................... 5 
2.3 
Risk/Benefit Assessment .................................................................................................................... 6 
2.3.1 
Known Potential Risks ..................................................................................................... 6 
2.3.2 
Known Potential Benefits ................................................................................................ 6 
2.3.3 
Assessment of Potential Risks and Benefits ................................................................ 6 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 7 
4 
STUDY DESIGN ............................................................................................................................................. 8 
4.1 
Overall Design ...................................................................................................................................... 8 
4.2 
Scientific Rationale for Study Design .............................................................................................. 10 
4.3 
Justification for Dose ......................................................................................................................... 10 
4.4 
End of Study Definition ..................................................................................................................... 11 
5 
STUDY POPULATION ................................................................................................................................ 11 
5.1 
Inclusion Criteria ................................................................................................................................ 11 
5.2 
Exclusion Criteria ............................................................................................................................... 11 
5.3 
Lifestyle Considerations .................................................................................................................... 11 
5.4 
Screen Failures .................................................................................................................................. 11 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 12 
6 
STUDY INTERVENTION ............................................................................................................................ 13 
6.1 
Study Intervention(s) Administration ............................................................................................... 13 
6.1.1 
Study Intervention Description ..................................................................................... 13 
6.1.2 
Dosing and Administration ............................................................................................ 13 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 13 
6.2.1 
Acquisition and accountability ...................................................................................... 13 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 14 
6.2.3 
Product Storage and Stability ....................................................................................... 14 
6.2.4 
Preparation ...................................................................................................................... 14 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 14 
6.4 
Study Intervention Compliance ........................................................................................................ 14 
6.5 
Concomitant Therapy ........................................................................................................................ 14 
6.5.1 
Rescue Medicine ............................................................................................................ 14 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 14 
7.1 
Discontinuation of Study Intervention ............................................................................................. 14 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 14 
7.3 
Lost to Follow-Up ............................................................................................................................... 15 
8 
STUDY ASSESSMENTS AND PROCEDURES ...................................................................................... 15 
8.1 
Efficacy Assessments ....................................................................................................................... 15 
8.2 
Safety and Other Assessments ....................................................................................................... 15 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 15 

  
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8.3.1 
Definition of Adverse Events (AE) ............................................................................... 15 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 16 
8.3.3 
Classification of an Adverse Event .............................................................................. 16 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 17 
8.3.5 
Adverse Event Reporting .............................................................................................. 18 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 19 
8.3.7 
Reporting Events to Participants ................................................................................. 19 
8.3.8 
Events of Special Interest ............................................................................................. 19 
8.3.9 
Reporting of Pregnancy ................................................................................................ 19 
8.4 
Unanticipated Problems .................................................................................................................... 19 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 19 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 20 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 20 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 20 
9.1 
Statistical Hypotheses ....................................................................................................................... 20 
9.2 
Sample Size Determination .............................................................................................................. 21 
9.3 
Populations for Analyses .................................................................................................................. 22 
9.4 
Statistical Analyses ............................................................................................................................ 22 
9.4.1 
General Approach ............................................................. Error! Bookmark not defined. 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 23 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 23 
9.4.4 
Safety Analyses .............................................................................................................. 24 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 24 
9.4.6 
Planned Interim Analyses ............................................................................................. 24 
9.4.7 
Sub-Group Analyses ..................................................................................................... 24 
9.4.8 
Tabulation of Individual participant Data .................................................................... 24 
9.4.9 
Exploratory Analyses ..................................................................................................... 24 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 25 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 25 
10.1.1 
Informed Consent Process ........................................................................................... 25 
10.1.2 
Study Discontinuation and Closure ............................................................................. 26 
10.1.3 
Confidentiality and Privacy ........................................................................................... 26 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 27 
10.1.5 
Key Roles and Study Governance .............................................................................. 28 
10.1.6 
Safety Oversight ............................................................................................................. 29 
10.1.7 
Clinical Monitoring .......................................................................................................... 29 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 29 
10.1.9 
Data Handling and Record Keeping ............................................................................ 30 
10.1.10 
Protocol Deviations ........................................................................................................ 31 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 32 
10.1.12 
Conflict of Interest Policy .............................................................................................. 32 
10.2 
Additional Considerations ................................................................................................................. 33 
10.3 
Abbreviations ...................................................................................................................................... 34 
10.4 
Protocol Amendment History ........................................................................................................... 36 
11 
REFERENCES ............................................................................................................................................. 38 
 

A SMART Approach to Treating Tobacco Use Disorder in Persons Living with HIV  
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STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
A SMART Approach to Treating Tobacco Use Disorder in Persons Living 
with HIV 
Study Description: 
The study aims to answer the main research question, what is the optimal, 
adaptive strategy to promote long-term (24 week) reduction in average 
cigarettes smoked per day among patients with HIV? 
Objectives: 
 
Primary Objective:  The first aim is to identify the optimal adaptive 
approach to promote a reduction in average cigarettes smoked per day 
among participants. 
 
Secondary Objectives: The second aim is to identify the impact of various 
tobacco treatment regimens on confirmed smoking abstinence and HIV-
related biomarkers over time, including promoting improvements in: 1) 
CD4 count; 2) HIV viral load suppression; and 3) VACS Index scores within 
participants. The third aim is to conduct an implementation focused-
evaluation of a pharmacist-delivered intervention involving NRT, VAR or 
Bupropion, and CM among all the stakeholders (clinicians, staff and 
leadership).  
Endpoints: 
Primary Endpoint: The primary endpoint will be reduction in average 
cigarettes smoked per day at 12 and 24 weeks. 
Secondary Endpoints: Verified 7-day smoking cessation and change in CD4 
count, HIV viral load and VACS index at 12 and 24 weeks for each 
treatment strategy. 
Study Population: 
18 to 64 Years, 65 Years and Over, Patients, MSSM Employees 

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Phase: 
N/A 
Description of 
Sites/Facilities Enrolling 
Participants: 
Mount Sinai Hospital, Yale New Haven Hospital, SUNY Downstate 
Description of Study 
Intervention: 
The purpose of this research study is to compare different strategies, 
involving medications (nicotine replacement therapy and varenicline or 
bupropion) and contingency management to help people with HIV reduce 
daily cigarettes smoked. 
Study Duration: 
10 years 
Participant Duration: 
24 weeks 
 
 
1.2 
SCHEMA 
 
 
 
 
 
 
 
 
 
Participants: 
PWH who 
smoke
NRT +          CM
Response
NRT +                               
CM
Non-response 
NRT + CM+
Varenicline or 
bupropion+ CM
NRT
Response
NRT
Non-response
NRT +
CM
Varenicline or 
bupropion

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
 
Instrument 
Baseline 
Week 
12 
Week 
24 
Intake History/Patient Demographics 
X 
  
  
Medical and psychiatric comorbidities 
X  
  
  
  
  
Impulsivity Scale 
X 
  
  
ASSIST 
X 
  
X 
PROMIS PROPr 
X 
X  
X 
Exhaled carbon monoxide level 
X 
X 
X 
Wisconsin Predicting Patients’ Relapse 
Questionnaire 
X 
X 
X 
Heaviness of Smoking Index 
X 
X 
X 
Self-report of tobacco use 
X 
X 
X 
E-cigarette use 
X 
X 
X 
HIV biomarkers (CD4 cell count, HIV viral load) 
X 
  
X 
VACS Index 2.0 
X 
  
X 
HIV Symptom Index 
X 
X 
X 
Treatment Service Review (TSR) 
X 
X 
X 
NRT and/or varenicline or bupropion  
adherence 
  
X 
X 
CM session attendance, draws and rewards 
earned 
X 
X 
X 
Cost-related data (cost of tobacco, medication 
co-pay) 
X 
X 
X 

A SMART Approach to Treating Tobacco Use Disorder in Persons Living with HIV  
Version 4.0 
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Patient Satisfaction Survey 
  
X 
X 
 
 
Study Visits- Ph=pharmacist Visits, CM=Contingency management visits and As=assessments  
 
 
If participants are unable to attend CM visits due to COVID-19 related restrictions and remote CO 
monitoring is not available we will accept the attestation, over the phone or in writing, from a family 
member, partner, or closest informant that they have not smoked in 7 days as a successful CM visit.  
 
In the event of shutdown of in-person human subjects research for studies that are non-COVID- related 
but have benefit, the study PI will contact any participants reaching key data collection milestones (week 
12 or week 24) and ask for permission to do a home visit to perform CO monitoring in an outdoor 
setting. The study team will perform this home visit if or when it is applicable.  Study team will also do 
remote CM visits with remote CO monitoring as indicated and if possible (i.e., participant has eCO 
monitor and needed technology). 
 
 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
The study aims to answer the main research question, what is the optimal, adaptive strategy to promote 
long-term (24 week)  reduction in average daily cigarettes smoked among patients with HIV? The first 
aim is to identify the optimal adaptive approach to promote reduction in average cigarettes smoked per 
day among participants. The second aim is to identify the impact of various tobacco treatment regimens 
on promoting confirmed smoking abstinence and HIV-related biomarkers over time, including promoting 
improvements in: 1) CD4 count; 2) HIV viral load suppression; and 3) VACS Index scores within 
participants. The third aim is to conduct an implementation focused-evaluation of a clinical pharmacist-
delivered intervention involving NRT, VAR, bupropion, and CM among all the stakeholders (clinicians, 
staff and leadership). Aim 3: To inform future implementation efforts of our clinical pharmacist-
delivered intervention involving NRT, CM and varenicline and bupropion to promote smoking cessation 
among patients with HIV, we will conduct a comprehensive evaluation of factors that may impact 
delivery of this intervention in real-world settings. This evaluation will be based on recruitment 
experiences; surveys from clinicians, staff, clinical leadership, social workers, psychologists, and care 
coordinators; and costs associated with the intervention. 
 

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2.2 
BACKGROUND  
 
Background 
 
Cigarette smoking is a major health threat to patients with HIV (PLWH). Cigarette smoke is uniquely 
harmful among PWH due to effects on HIV and the immune system. The Veterans Aging Cohort Study 
(VACS) Index, a validated measure that predicts morbidity and mortality risk, correlates with markers of 
inflammation, is responsive to smoking status, and may serve as an outcome in intervention studies. 
Smoking cessation is consistently recommended for PWH, yet current approaches are inadequate. There 
is a potential role for clinical pharmacists in delivering smoking cessation treatment in HIV treatment 
settings. Nicotine replacement therapy (NRT), varenicline (VAR) and bupropion are effective treatments 
and safe in HIV. Contingency management (CM) promotes smoking cessation and has been used with 
PWH. Adaptive treatment regimens (ATRs) that are responsive to patients' needs and outcomes may be 
more effective than static pathways for addressing tobacco use. An important gap in our understanding 
of tobacco treatment among PWH is the lack of an evidence-based ATR. The overarching goal of this 
study is to identify such a regimen with the Sequential Multiple Assignment Randomized Trial (SMART) 
design, which allows adjustments in treatment according to patient response, and to develop optimal 
regimens. 
 
Primary and Secondary Study Endpoints 
 
Aim 1: The primary endpoint will be mean number of cigarettes smoked per day. Tobacco use will be 
assessed by self-report.). 
 
To complete Aim 1, we will evaluate the impact of the initial treatment strategy on 12 week mean 
number of cigarettes smoked per day and, among participants who do not respond at week 12, evaluate 
the impact of switching from NRT to an oral medication (varenicline or bupropion) compared to 
intensifying contingency management on 24 week mean number of cigarettes smoked per day. We will 
then identify the optimal treatment strategy. 
 
Aim 2. For secondary outcomes, we will assess smoking abstinence by both self-report and confirmatory 
biochemical testing with exhaled carbon monoxide (eCO) or verification of abstinence by closest 
informant (if unable to obtain eCO.) To assess the impact of the smoking cessation treatment strategies 
on HIV outcomes, we will examine change in CD4 count, HIV viral load and VACS index at 12 and 24 
weeks for each treatment strategy.  
 
Aim 3: We will conduct a survey upon initiation of the RCT and post-RCT to assess knowledge, attitudes 
and practice of a clinical pharmacist-delivered smoking cessation intervention involving medications and 
contingency management, including the 12-item Organization Readiness for Implementation Change 
(ORIC) assessment and Contingency Management Beliefs Questionnaire (CMBQ). The ORIC has been 
widely applied to the evaluation of interventions intended to promote evidence-based practices. The 
CMBQ has been validated to assess factors impacting implementation of CM. Differences in pre-post 
trial responses in the survey items will be assessed using appropriate parametric or non-parametric 
methods.  We will assess cost variation based on potential other providers of the intervention (e.g., 
physician, nurse, advanced practice practitioner, social worker). We will assess participant satisfaction 
with the intervention at week 24. 
 

A SMART Approach to Treating Tobacco Use Disorder in Persons Living with HIV  
Version 4.0 
Protocol IRB-19-02585 
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2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
Potential participants will be informed about the study by screening processes and/or while they are 
present in clinic for a routine visit. They will be asked how they would prefer to be contacted in the 
future (in person, by telephone, by text, or by email). Participants will be fully informed of all possible 
study procedures and will be notified that they may withdraw from the study at any time without any 
effect on their health care. In addition, participants have the option to skip any questions that may 
cause them discomfort. 
Blood samples will be collected as part of the standard of care in the clinics; these results will be utilized 
for this study, but no additional study-only phlebotomies are planned. Breath samples to assess carbon 
monoxide levels 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 participants, 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 participants' confidentiality. The alternative to participation is for a potential 
participant to decide NOT to participate.  
2.3.2 KNOWN POTENTIAL BENEFITS  
 
Possible benefits may be that the participant is able to stop smoking, which may greatly improve their 
overall health. In addition, this study will generate new information about the role for clinical 
pharmacists in optimizing strategies to help people with HIV stop smoking. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
The main risks to the participant are possible side effects to nicotine replacement therapy, varenicline or 
bupropion.  
• 
NRT: There is a very small risk of nicotine toxicity, if nicotine replacement products are used in 
higher quantities than prescribed or from smoking while using the products. Symptoms of 
nicotine toxicity include cold sweats, fainting, confusion, or pounding heart. The Food and Drug 
Administration (FDA) has published new guidelines, which suggest that these products are safe 
to use longer than 12 weeks. Based on the study design, the risks of toxicity are minimized by 
having the clinical pharmacist prescribe the dosage of nicotine replacement therapy based on 
how much the participant smokes daily.  
• 
Varenicline: The main risks of varenicline are nausea at onset of use that is generally mitigated 
by taking before meals and usually abates over time. Sleep disturbance, including vivid dreams, 
has been reported. Less common effects include indigestion, abdominal pain, and gas, fatigue, 
headache and dry mouth.  
• 
Bupropion: The main risks of bupropion include increased risk of seizure; thus, it should be 
avoided in patient with an underlying seizure disorder, eating disorder, untreated alcohol use 
disorder, and/or concurrent use of a monoamine oxidase inhibitor (MAOI). Common side effects 
may include insomnia, dry mouth, and constipation. Uncommon side effects may include rash, 
itching or hives. The medicine may also cause dizziness; thus, individuals should avoid driving or 

A SMART Approach to Treating Tobacco Use Disorder in Persons Living with HIV  
Version 4.0 
Protocol IRB-19-02585 
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using heavy machinery before they know how they might react. The medicine may also cause 
some patients to have abnormal behaviors or worsening mood or suicidal thoughts. Participants 
will be instructed to report any of these symptoms immediately to the research team. 
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
 
Aim 1: The primary endpoint will 
be mean of cigarettes smoked per 
day. .  
 
 
 
Tobacco use will be assessed by self-
report  
 
To complete Aim 1, we will evaluate 
the impact of the initial treatment 
strategy on 12-week  mean number 
of cigarettes per day  and, among 
participants who do not respond at 
week 12, evaluate the impact of 
switching from NRT to varenicline or 
bupropion compared to intensifying 
contingency management on 24-
week mean number of cigarettes per 
day.  
 
 
This endpoint was 
chosen to identify the 
optimal treatment 
strategy on promoting 
harm reduction from 
tobacco use.  
Secondary 
 
 
 
Aim 2. For secondary outcomes 
and to assess the impact of the 
smoking cessation treatment 
strategies tobacco abstinence and 
on HIV outcomes.  
 
 
We will evaluate abstinence by 
confirmatory biochemical testing 
with eCO or verification by close 
informant. 
 
We will examine change in CD4 
count, HIV viral load and VACS index 
at 12 and 24 weeks for each 
treatment strategy. 
 
 
This endpoint was 
chosen to see if and 
how the treatment 
strategies promote 
abstinence and 
whether smoking 
cessation treatment 
affects HIV outcomes. 
 
Tertiary/Exploratory  
 
 
 
Aim 3: We will conduct a survey 
upon initiation of the RCT and post-
RCT.  
 
 
We will conduct a survey upon 
initiation of the RCT and post-RCT, 
including the 12-item Organization 
Readiness for Implementation 
Change (ORIC) assessment and 
Contingency Management Beliefs 
Questionnaire (CMBQ). The ORIC has 
been widely applied to the evaluation 
 
To assess knowledge, 
attitudes and practice 
of a clinical pharmacist-
delivered smoking 
cessation intervention 
involving medications 
and contingency 
management and  

A SMART Approach to Treating Tobacco Use Disorder in Persons Living with HIV  
Version 4.0 
Protocol IRB-19-02585 
12 December 2022 
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
 
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4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
Description of the Study Design 
To address aims 1 and 2, we plan to use a two-arm, two-stage randomized trial design of 632 patients 
with HIV who smoke cigarettes and receive their HIV care in one of three health systems. 
To address aim 3, we plan to hold pre- and post-trial surveys involving clinicians, staff, clinical 
leadership, social workers, psychologists, and care coordinators to conduct an implementation focused-
evaluation of a clinical pharmacist-delivered intervention. 
 
Description of Procedures Being Performed 
For aims 1 and 2, at baseline, intake history, demographics, questionnaires relating to depression, drug 
and alcohol problems, smoking habits, medication adherence, HIV symptoms and quality of life will be 
performed. The depression, substance use, quality of life questionnaires, HIV symptom index and costs 
related to tobacco use and clinic travel will be administered at weeks 12 and 24. Tobacco measures will 
be performed at all time points - relating to carbon monoxide levels, cigarette consumption, nicotine 
dependence, tobacco use and e-cigarette use. HIV related measures pertaining to CD4 count, viral load 
and other lab values, health care utilization (ED visits, hospitalizations), and treatment services to 
address tobacco use will be collected at baseline, week 24 and month 12. Patient satisfaction, opinions 
about services and adherence will also be recorded. At baseline, participants will be randomized 1:1 to 
either NRT (nicotine replacement therapy) or NRT + CM. Participants will receive a prescription for 12 
weeks of the long-acting NRT patches and short-acting NRT (i.e., gum, lozenges, an inhaler or spray) with 
standard advice. Participants will fill the prescription through their usual pharmacy of choice. 
Participants will be invited to complete five follow-up visits with the clinical pharmacist over the 
following 12 weeks to address medication adherence, side effects and review progress in achieving 
smoking abstinence. For those randomized to additionally receive contingency management (CM), these 
visits will be integrated into the sessions with the clinical pharmacist. At week 12, participants who 
responded to initial treatment will continue without change. Participants who do not respond to the 
intervention, will be re-randomized, to switch to either VAR or bupropion or intensify to CM+. 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
of interventions intended to promote 
evidence-based practices. and the 
CMBQ has been validated to assess 
factors impacting implementation of 
CM. Differences in pre-post trial 
responses in the survey items will be 
assessed using appropriate 
parametric or non-parametric 
methods.  
to assess cost variation 
based on potential 
other providers of the 
intervention (e.g., 
physician, nurse, 
advance practice 
practitioner, social 
worker). We will assess 
participant satisfaction 
with the intervention 
at week 24. 
 

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Participants will be invited to return to visit the clinical pharmacist for an additional 5 visits, with the 
final visit at week 24. All of the CM sessions will be audio recorded and reviewed to ensure compliance 
with management strategies. NRT only sessions will also be recorded and a random sample (10-20%) will 
be reviewed to also ensure fidelity to the protocol and to provide feedback to the clinical pharmacists. 
No video recording will occur. Dr. David Ledgerwood, the CM consultant on the project, will be primarily 
responsible for reviewing the recordings. The audio files will be sent to the Coordinating Center via the 
Yale OneDrivesystem, which encrypts the recordings. The files will not contain names or other 
identifying information. The audio files will be stored on Yale Secure Box; only Dr. Edelman, Dr. 
Bernstein, and Dr. Ledgerwood will have access to the folder. A random sample of the audio files may be 
transcribed via professional transcription services to allow for qualitative analysis. The recordings will be 
destroyed after 6 years.  
 
For aim 3, all clinicians, staff, clinical leadership, social workers, psychologists, and care coordinators 
employed at the participating site will be invited to complete the brief surveys pre- and post- trial 
intervention, administered through REDCap and distributed via email. The survey will assess knowledge, 
attitudes and practices that may impact implementation of a clinical pharmacist delivered intervention 
involving medications and CM and will be modeled after the ORIC and CMBQ and other surveys.  
 
To maintain safety procedures, in some circumstances, patients can participate in study 
activities/counseling, and undergo surveys and be consented for the study, via video conferencing link 
or phone. Patients will be given a link to video conference with provider/clinical pharmacist/coordinator 
to maintain social distancing guidelines. Zoom version provided is HIPAA compliant per Sinai. Or if using 
phone for study procedures, patients will be contacted via the phone number they provided. 
 
Description of the Source Records that Will Be Used to Collect Data About Subjects 
Participants will be verbally asked during pre-screening (in person and/or phone screening) whether we 
can collect and store some demographic data and the answers to their pre-screening questions. 
Information from the phone and in person screeners will (1) only be used to determine eligibility, (2) will 
not be included in study analyses other than to determine (a) the proportion of eligibility among persons 
approached (b) the characteristics of those who decline to participate among those eligible. This will be 
done using HIPAA compliant Zoom Phone. Pre-screening questions include current and lifetime smoking 
habits, language spoken, study eligibility, demographic questions include age, gender, race, ethnicity. 
This information will be captured in REDCap with no identifiers. For Aims 1 and 2, electronic medical 
records, lab results, questionnaire answers, responses on measures, will all be used to provide data 
about the participants. 
 
Primary Care provider records: 
- HIV/AIDS status, hepatitis infection status, sexually transmitted diseases, physical exam (height, 
weight, blood pressure), diagnosis and treatment of medical and psychiatric conditions, sexual practices, 
tobacco and alcohol use, use of drugs, smoking status and habits, medication list, pregnancy status, 
language abilities, adverse events, side effects, transportation 
 
Specialist provider records: 
- HIV/AIDs status, hepatitis infection status, sexually transmitted diseases, physical exam (height, 
weight, blood pressure), diagnosis and treatment of medical and psychiatric conditions, sexual practices, 
tobacco and alcohol use, use of illegal drugs, smoking status and habits, medication list, adverse events, 
side effects, transportation, time/costs travel to clinic 
 

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Laboratory records, other test results, and treatment services:  
CD4 count, hepatitis infection status, sexually transmitted disease, viral load, creatinine, hemoglobin, 
WBC, eGFR, albumin, platelets, AST, ALT, Body-mass index, tobacco treatment services, hospitalizations, 
and emergency department visits. 
 
Psychiatrist/therapy records:  
-as needed to help determine presence of an unstable psychiatric condition and whether patient meets 
exclusion criteria, phone call records: diagnosis and treatment of medical and psychiatric conditions, 
adverse events, side effects  
 
Demographics from electronic medical record: 
-First name, last name, gender, date of birth, MRN, telephone number, employment status, insurance, 
income, self-identified gender identity, race, ethnicity, education, mailing address, proxies/alternate 
contacts 
 
For Aim 3, survey data will be collected in a confidential fashion and administered through REDCap. The 
ORIC has been applied to the evaluation of interventions intended to promote evidence-based practices, 
and the CMBQ is a validated measure to assess providers' perspectives regarding CM. Information will 
be collected to allow for linkage pre and post survey data and measure change in responses. 
 
Description of Data that Will Be Collected Including Long-Term Follow-Up 
There will not be any long term follow up for Aims 1 & 2 except for the 12 month chart review for lab 
data and treatment services. 
For Aim 3, in year 5, the post-trial survey will be sent out. The same information will be collected during 
the post-trial survey. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
There are no potential problems associated with the control group chosen in light of the SMARTTT 
intervention. 
 
4.3 
JUSTIFICATION FOR DOSE 
 
Prescribe dosing of patch based on patient’s level of tobacco use  
5-9 cigarettes per day: 14mg patch 
>10 cigarettes per day: 21mg patch 
 
Prescribe short-acting NRT based on timing of first daily cigarette: 
First cigarette is within 30 minutes of waking: 4mg 
First cigarette is after 30 minutes of waking: 2mg 
 
Varenicline and bupropion dosing is prescribed per standard clinical guidelines and at the discretion of 
the clinical pharmacist.  
 
Varenicline: 0.5 mg each day for 3 days, then -0.5 mg twice per day for 4 days, then 1mg twice per day. 
 

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Bupropion: 150 mg for 3 days, then 150mg twice per day. 
 
4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), 
Section 1.3. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
Inclusion Criteria 
 
For Aims 1 and 2: Patients will be eligible for study entry if they: 1. are HIV positive; 2. Receive care at 1 
of the participating sites; 3. are >=18 years old; 4. have smoked >=100 cigarettes lifetime; 5. report 
smoking every day or some days; 6. smoke, on average, >=5 cigarettes per day; and 7. provide written 
informed consent. A HIPAA waiver will be requested to allow prescreening via patient chart review.  
 
For Aim 3: All clinicians, staff, clinical leadership, social workers, psychologists, and care coordinators 
employed at the participating site will be invited to complete the brief surveys pre- and post- trial 
intervention. Survey data will be collected in a confidential fashion and administered through REDCap. 
Surveys will be distributed by email and clinicians and staff will be informed and encouraged to 
participate by clinical leadership. An alteration of written informed consent will be requested for Aim 3. 
 
5.2 
EXCLUSION CRITERIA 
Exclusion Criteria 
 
For Aims 1 and 2: Patients will be excluded for: 1. exclusive use of non-cigarette tobacco or nicotine 
products, including e-cigarettes; 2. current use of NRT, VAR, or bupropion (defined as use of medication 
in prior 7 days); 3. self-report or urine testing confirming pregnancy, nursing, or trying to conceive; 4. 
Life-threatening or unstable medical, surgical, or psychiatric condition; 5. inability to provide at least 1 
collateral contact for a friend or family member; 6. living out-of-state; or 7. inability to read or 
understand English or Spanish.  
 
For Aim 3: Participants will be excluded for 1) less than 18 years of age and 2) NOT employed at the HIV 
clinic. 
 
Enrollment Restrictions Based Upon Gender, Pregnancy, Childbearing Potential, or Race 
Yes 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
If the participant is a woman and wants to take part of the study, they need to use birth control while 
they are participating in the study. 
 
5.4 
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People who are pre-screened are assigned a study ID will be tracked so we know who is eligible and 
ineligible.  
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
How Participants Will Be Identified 
 
For Aims 1 and 2, potential participants will be identified by chart review or via data reports filtered on 
eligibility criteria, in advance of the clinic.  We will develop recruitment flyers specific to each site . 
Potential participants may be referred to the study team by a clinic provider or staff member. In 
addition, eligible patients may be informed about the study by messaging via medical record as 
applicable at a given site (e.g., Epic MyChart). Patients may also self-refer after hearing about the study 
from a public service announcement in the clinic waiting room.  
 
For Aim 3, all clinicians, staff, clinical leadership, social workers, psychologists, and care coordinators 
employed at the participating site will be invited to complete the brief surveys pre- and post- trial 
intervention. 
 
 
Who Will Initially Approach Potential Participants  
 
Study Personnel 
 
How Research Will Be Introduced to Participants 
 
Potentially eligible patients may be recruited via multiple pathways: 
1. Direct referral by clinic provider or staff; 
2. Self-referral based on recruitment flyer, peer, or otherwise; 
3. Proactive, opt-out recruitment based on electronic medical record review, followed by mailed 
letter and, if the patient does not opt out of being called, research team outreach; and/or 
4. Messaging through the secure medical record with invitation to participate as available at a 
given site and per site policies.   
5. Self-referral via a public service announcement on video monitors in the clinic waiting room.  
 
Individuals who meet inclusion and exclusion criteria and provide written consent to participate will 
have baseline assessments performed, and then will be randomized 1:1 to either NRT or NRT+CM. 
 
For the Yale New Haven Hospital site only (Aims 1 and 2): 
 
To assist in recruitment, the Yale Clinical Center for Investigation (YCCI) will help to identify potential 
eligible participants. The YCCI team will mail recruitment letters and post social media advertisements.  
In addition, they will send announcements through the Help Us Discover database, which contains 
several thousand individuals who volunteer for clinical research.  Additionally, they will send messages 
through the secure messaging system through the medical record (MyChart via Epic) for those patients 
who have opted in to being contacted for clinical research studies.  
 
For the SUNY/Downstate site only (Aims 1 and 2): 

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A public service announcement (PSA) will play on a loop on video monitors in clinic waiting areas. The 
PSA will give a brief description of the study and will include a contact telephone number for patients to 
contact the study team.  
 
For Aim 3, all clinicians, staff, clinical leadership, social workers, psychologists, and care coordinators 
employed at the participating site will be invited to complete the brief surveys pre- and post- trial 
intervention. The pre-trial survey will occur within the first 3 months of the RCT launch; the post-trial 
survey will occur within the last three months of the RCT completion. 
 
6 
STUDY INTERVENTION 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
Refer to these documents that were submitted and approved by the IRB: 
Nicorette insert 
Nicorette lozenge insert 
Nicorette patch insert 
Varenicline (Chantix) insert 
Bupropion 
6.1.2 DOSING AND ADMINISTRATION 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
The clinical pharmacist during the study visit will control the product (based on the images of the drugs 
that we submitted and were approve by the IRB) based on how much the participant smokes: 
 
Prescribe dosing of patch based on patient’s level of tobacco use  
5-9 cigarettes per day: 14mg patch 
>10 cigarettes per day: 21mg patch 
 
Prescribe short-acting NRT based on timing of first daily cigarette: 
First cigarette is within 30 minutes of waking: 4mg 
First cigarette is after 30 minutes of waking: 2mg 
 
Prescribe varenicline as follows: 
Days 1-3: 0.5 mg once per day 
Days 4-7: 0.5 mg twice per day 
Day 8 until end of treatment: 1 mg twice per day 
 
Prescribe bupropion as follows: 
Days 1-3: 150mg per day 
Day 4 until end of treatment: 150mg twice per day 

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6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Refer to sections 6.1.1 and 6.2.1 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
N/A 
 
 
6.2.4 PREPARATION 
 
N/A 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Randomization is conducted through REDCap, clinical trials data management system. Participants, 
clinical pharmacists, nor research coordinators are blinded to treatment condition.  
 
6.4 
STUDY INTERVENTION COMPLIANCE 
Study intervention compliance will be recorded in REDCap based on self-reported information of 
medication and compliance will be measured based on participants showing up to pharmacy visits which 
will also be recorded on REDCap. 
  
6.5 
CONCOMITANT THERAPY 
6.5.1 RESCUE MEDICINE  
N/A 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
The intervention may be discontinued if a participant has adverse effects from the prescribed 
medications. However, the participant will remain in the study for follow-up assessments.  
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Anticipated Circumstances of Subject Withdrawal 
 
Participants may be withdrawn from the research without their consent if they are deemed ineligible for 
the study. Participants may also be withdrawn from the research if they have experienced serious or 
related adverse events. If any participant asks to withdraw from the study, they will be notified that 
medical record data collection will continue, but any interventional procedures may cease. If a 
participant asks for complete withdrawal from the study, he or she must do so by written notification to 
the site-PI. 
 
 

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Procedures for Subjects to Request Withdrawal 
 
If any participant asks to withdraw from the study, they will be notified that medical record data 
collection will continue, but any interventional procedures may cease. If a participant asks for complete 
withdrawal from the study, they must do so by written notification to the site PI. 
 
Procedures for Investigator to Withdraw Subjects 
Participants may be withdrawn from the research without their consent if they are deemed ineligible for 
the study. Participants may also be withdrawn from the research if they have experienced serious or 
related adverse events. If participants are lost to follow-up, they will not be withdrawn. We will try to 
continue to get assessments through 24 weeks and complete data collection via the electronic medical 
record, unless consent is withdrawn in writing. 
 
7.3 
LOST TO FOLLOW-UP 
 
Site staff will make every effort to contact study participants, including calling and texting alternate 
telephone numbers using the Zoom Phone application. In addition, site staff will try to meet participants 
when they are in clinic for their regular visits with their providers. If they are unable to reach a 
participant, a letter will be sent to their last known mailing address. Participants should not be 
considered lost to follow up until 6 months after the 24 weeks have elapsed.  
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
EFFICACY ASSESSMENTS  
 
We will have participants do labs to study the longitudinal impact of smoking on the Veterans Aging 
Cohort Study (VACS) Index, a validated measure that predicts morbidity and mortality risk.  Based on 
routinely collected lab tests (CD4 count, HIV viral load, hemoglobin, AST, ALT, platelets, creatinine, and 
HCV status, albumin, white blood cell count), the VACS Index correlates with measures of inflammation, 
microbial translocation, and impaired T cell activation known to be elevated with HIV and smoking.  
Exhaled carbon monoxide testing will also be collected to confirm abstinence. 
 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
In this study we will collect lab work from participants that includes their physical examinations, CD4 
count, viral load, diagnostic labs (metabolic panel) and eCO. 
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
Grading System to Evaluate 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. 

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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 
 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 SEVERITY OF EVENT 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”.] 
 
Grading System to Evaluate Adverse Events 
The following scale will be used in grading the severity of adverse events noted during the study: 
1. Mild adverse event: Events require minimal or no treatment and do not interfere with the 
participant’s daily activities.  
2. Moderate adverse event: Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with functioning. 
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 
 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  

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• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
OR 
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician.] 
 
 
8.3.3.3 EXPECTEDNESS  
Site PI will be responsible for determining whether an adverse event (AE) is expected or unexpected.  An 
AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent with 
the risk information previously described for the study intervention. 
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 

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The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The site-PIs will record all reportable events with start dates occurring any time after informed consent 
is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation.  At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events 
will be followed for outcome information until resolution or stabilization. 
 
 
8.3.5 ADVERSE EVENT REPORTING  
 
The principal investigators (E. Jennifer Edelman, MD, MHS and Steven L. Bernstein, MD) will conduct a 
review of all adverse events upon completion of every study participant. The MPIs will evaluate the 
frequency and severity of the adverse events and determine if modifications to the protocol or consent 
form are required. Dr. Keith Sigel will be responsible for IRB approval and for monitoring day-to-day 
study activities at the Mount Sinai site. Dr. Jessica Yager will be responsible for study activities at STAR.     
 
Selection Procedures to Minimize Toxicity 
 
Symptoms associate 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. 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. Patients using the nicotine inhaler may 
experience cough. There is also a very small risk that the participant could have an allergic reaction to 
the drug in any of these products. If this occurs, the participant will be asked to notify the study team at 
once and seek immediate medical attention. Symptoms of an allergic reaction include rash, itching, 
swelling, dizziness, and trouble breathing. 

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VAR may cause nausea in some users, generally mitigated by taking before meals, and usually abating 
over time. Sleep disturbance, including vivid dreams, have been reported. Less common side effects 
include indigestion, abdominal pain and gas, fatigue, headache, and dry mouth. If these occur, the 
research participant will be asked to notify study personnel. 
 
The main risks of bupropion include increased risk of seizure thus it should be used with caution in 
patient with an underlying seizure disorder, eating disorder, untreated alcohol use disorder, and/or 
concurrent use of a monoamine oxidase inhibitor (MAOI). Common side effects may include insomnia, 
dry mouth, and constipation. Uncommon side effects may include rash, itching or hives. The medicine 
may also cause dizziness thus individuals should avoid driving or using heavy machinery before they 
know how they might react. The medicine may also cause some patients to have abnormal behaviors or 
worsening mood or suicidal thoughts. Participants will be instructed to report any of these symptoms 
immediately to the research team. 
 
 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
Serious adverse events, whether related or unrelated, will be reported to the MPIs and the IRB as soon 
as study staff become aware of the event.  
 
Reporting Events to Participants  
Study participants will be notified individually of any new findings or adverse events which may affect 
their participation in the trial.  
 
8.3.7 EVENTS OF SPECIAL INTEREST  
 
N/A 
 
8.3.8 REPORTING OF PREGNANCY  
 
Prior to study participation, potential female participants are counseled to use birth control to prevent 
pregnancy during the trial. If a female participant becomes pregnant while on study, the PIs will 
determine if she should continue on study medication.  
  
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
 
If any new risks to participants are identified, the following steps may be taken: 
1. Modification of inclusion/exclusion criteria 
2. Suspension of new enrollment or halting of study procedures for enrolled participants 
3. Modification of informed consent document and/or protocol to include an explanation of the 
newly recognized risks. 
4. Provision of additional information about newly recognized risks to enrolled participants. 
 

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Unanticipated problems may include any incident, experience, or outcome that meets the following 
criteria: 
1. Unexpected in nature, severity, or frequency 
2. Related or possibly related to study participation 
3. Research participants or others are put at a greater risk of physical, psychological, economic, or 
social harm not previously known.  
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
The PI will report any unanticipated problem to the IRB and to the lead PI and include the following 
information: 
1. Protocol number and title, name of PI 
2. A detailed description of the event, incident, experience, or outcome. 
3. A description of any necessary changes to the protocol or other corrective actions taken or 
proposed.  
 
Unanticipated problems which are SAEs will be reported to the IRB and the lead PI with 48 hours of the 
PI becoming aware of the event. Unanticipated problems which are not serious will be reported within 7 
days of the PI becoming aware of the event. In addition, the lead PI will report the unanticipated 
problem to the study sponsor as appropriate.  
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Study participants will be individually notified of unanticipated problems if there are risks to their health 
or to their participation in the trial. 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
• 
Primary Efficacy Endpoint(s):  
 
For our first primary hypothesis (Aim 1, Hypothesis 1), we will evaluate the impact of the initial 
treatment strategy (NRT vs NRT+CM) on daily cigarette consumption (self-reported mean cigarettes per 
day) at 12 weeks. We hypothesize that those receiving NRT+CM will have lower daily cigarettes 
consumed compared to those receiving only NRT.  
 
In those not responding to the initial treatment, our second primary hypothesis is that switching to oral 
medication will lead to a greater reduction in average cigarettes per day at 24 weeks when compared to 
intensifying CM.  
 
 
• 
Secondary Efficacy Endpoint(s): 
 
We hypothesize that: 
 

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1) NRT+CM will be associated with higher rates of confirmed abstinence at 12 weeks compared to 
NRT only. 
2) Among participants who do not respond to first stage treatment, switch to oral medication will 
be associate with higher rates of confirmed abstinence at 24 weeks compared to participants 
intensifying CM. 
 
We do not have a priori hypotheses about HIV outcomes (i.e., CD4, HIV viral load, VACS Index) but will 
estimate the impact of the sequential treatment strategies on these outcomes. 
 
 
 
 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
Power and sample size calculation. Our initial sample size calculations (see below) based on abstinence 
at 12 and 24 weeks required a sample size of 632 randomized participants to achieve 85% power for our 
2 primary hypotheses. As a sample size of 632 is not achievable within the timeframe of this study, we 
have altered the primary aims by changing the primary outcome to cigarette consumption (i.e. average 
cigarettes per day). We now hypothesize  that NRT+CM will be superior to NRT alone in reducing 
average cigarettes per day (H1). Similarly, in those that do not respond to first treatment (i.e. are not 
abstinent), we hypothesize that switching will be superior to intensifying in reducing average cigarettes 
per day (H2). Our baseline data shows a daily cigarette consumption of 13 (SD=7). We currently have 
randomized 187 participants which translates to a rate of ~8 per month. The following table 
demonstrates the detectable effect sizes (i.e. difference in mean number of cigarettes per day) for H1 
and H2 at 80 and 90% power for different enrollment months and number of subjects enrolled per 
month. The calculations used a signifance level of 0.025 (two-sided), a loss to follow-up of 20% and a a 
non-response rate of 88.5% for H2. The sample size calculations were performed with PASS v12 
(Kaysville, UT). 
Remaining 
Enrollment 
Months
Enroll Rate 
(Subjects/
Month)
Projected 
N 
Non-response 
Rate
Projected Non-
responders
Lost-to-
Follow-up
Detectable 
Cigs/Day         
(80% power)
Detectable 
Cigs/Day      
(90% power)
Detectable 
Cigs/Day      (80% 
power)
Detectable 
Cigs/Day        
(90% power)
19
5
282
0.885
250
0.2
2.90
3.31
3.07
3.51
6
301
0.885
266
0.2
2.80
3.20
2.98
3.41
7
320
0.885
283
0.2
2.71
3.10
2.89
3.30
8
339
0.885
300
0.2
2.64
3.02
2.80
3.20
9
358
0.885
317
0.2
2.56
2.93
2.72
3.11
10
377
0.885
334
0.2
2.50
2.86
2.65
3.03
24
5
307
0.885
272
0.2
2.78
3.17
2.94
3.36
6
331
0.885
293
0.2
2.67
3.05
2.84
3.24
7
355
0.885
314
0.2
2.57
2.94
2.73
3.12
8
379
0.885
335
0.2
2.49
2.85
2.65
3.03
9
403
0.885
357
0.2
2.41
2.76
0.04
2.93
10
427
0.885
378
0.2
2.34
2.68
2.49
2.85
1st Randomization (H1)
2nd Randomization (H2)            
(Non-responders)
 

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Given the expected 19 months of enrollment and anticipated 5 participants per month, we will have 
80% power to detect differences for the first randomization of 2.90 cigarettes per day and 3.07 
cigarettes per day for the second randomization. 
 
Original Sample Size Calculation: The overall goal of this proposal is to identify the optimal dynamic 
treatment strategy for PWH who smoke cigarettes. The primary aims are to identify the most efficacious 
initial treatment (Aim 1, H1), verified with measurement of eCO or by next closest informant at 12 weeks, 
and the most efficacious treatment (switch vs intensify) for non-responders (i.e. participants who 
continue to smoke) to the initial randomization (Aim 2, H2), verified with measurement of eCO or by next 
closet informant at week 24. For the effect sizes of the treatments, VAR, combination NRT, and CM, we 
use effect sizes taken from a Cochrane meta-analysis of tobacco dependence treatment in PLWH, 
focusing on data pooled from 11 clinical trials involving a total of 1785 participants. In these studies, 
tobacco dependence treatment interventions (behavioral, pharmacologic, or both) had a Mantel-
Haenszel risk of abstinence at up to 6 months, relative to controls, of 1.51 (95%CI 1.15, 2.00).1 An 
additional Cochrane meta-analysis of incentive payments for smoking cessation in general populations of 
adult smokers, pooling data from 17 trials involving 7715 participants, found an odds ratio for 
abstinence at 6 months or more of 1.42 (95%CI 1.19, 1.69), relative to controls.2 Using estimates from 
these studies, we assume a 12 week biochemically confirmed abstinence rate of 
16% for the first-stage treatment of combination NRT+CM, and 7% for NRT alone. For the second stage, 
in which non-responders from both NRT and NRT+CM arms are randomized to 12 weeks of either 
switching medication or intensifying CM, we assume an end-of-treatment biochemically confirmed 
abstinence rate of 16% for switching, and 7% for intensifying. Given these parameters and a 2-sided type 
I error of 0.025 (corrected for 2 primary hypotheses) a total sample size of 538 participants will provide 
85% power to detect superiority of NRT+CM over NRT alone for initial treatment. To account for a 15% 
loss to attrition, we will enroll a total of 632 participants. Given the expected proportions of non-
response to initial treatment (i.e. 88.5% total; 84% and 93% in NRT+CM and NRT alone respectively), the 
sample size will provide 80% power to detect a difference of 9% (i.e. 16% in switch, 7% in intensify). The 
sample size calculation was performed with PASS v12 (Kaysville, UT). Analysis for Aim 1. Primary Study 
Endpoints and Analyses. The primary efficacy endpoint for this study will be biochemically verified 7-day 
cessation at 12 weeks (Hypothesis 1) and 24 weeks (Hypothesis 2).3 Tobacco use will be assessed by self-
report and confirmatory biochemical testing with exhaled carbon monoxide.  
 
 
 
9.3 
POPULATIONS FOR ANALYSES 
 
Intention to treat – all randomized participants will be included in the primary analysis of average 
cigarettes per day provided they have an assessment at either baseline and/or follow-up. In addition, all 
randomized participants will be included in the denominator for calculating abstinence rates with the 
exception of unavoidable loss to follow-up. This will include 1) participants who have died and 2) those 
documented to have moved to an untraceable address. We will report the number of participants in 
these categories who are excluded separately for each condition.4 Multiple imputation will be used to 
account for missing data in those who decline to be involved in subsequent data collection. 
 
 
9.4 
STATISTICAL ANALYSES 
 

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9.4.1 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
For our first primary hypothesis (Aim 1, Hypothesis 1), we will evaluate the impact of the initial 
treatment strategy (NRT vs NRT+CM) on daily cigarette consumption (self-reported average cigarettes 
per day) at 12 weeks. We hypothesize that those receiving NRT+CM will have lower daily cigarettes 
consumed compared to those receiving only NRT. A repeated measures mixed model will be used to 
compare the two treatment groups. The mixed model will jointly model baseline and 12-week daily 
cigarette consumption and will allow for the inclusion of all participants with at least one smoking 
assessment (Carpenter 2007). The model will include fixed effects for time and the interaction of 
treatment and time (i.e. no main effect of treatment) as well as age, gender and HSI. Random effects will 
be included for subject and site. Linear contrasts will be used to compare the difference between groups 
for week 12. This difference will be conditional on baseline consumption and is equivalent to an analysis 
adjusted for baseline (Carpenter 2007). The difference in 12 week cigarette consumption between 
treatment groups will be evaluated at the 0.025 significance level (i.e. Bonferroni corrected for the 2 
primary hypotheses). 97.5% CIs will be estimated for treatment differences at week 12. 
 
A similar repeated measures mixed model analysis will be used for our other primary hypothesis (Aim 1, 
Hypothesis 2), to evaluate the impact of the second randomization (i.e. switch vs intensify) in non-
responders on average cigarettes per day. This analysis will only include participants who were non-
responders to the initial treatment. For those non-responders initially randomized to NRT, switching 
refers to receiving VAR or bupropion in the second randomization while intensifying refers to receiving 
NRT+CM. For those non-responders initially randomized to NRT+CM, switching refers to receiving VAR 
or bupropion+CM in the second randomization while intensifying refers to receiving NRT+CM+. The 
repeated measures mixed model will include second stage treatment as well as covariates for site, age, 
gender, HSI, reason for 12-week non-response (i.e. non-abstainer vs. loss to follow-up) and initial 
treatment group. Differences in average cigarettes per day at 24 weeks and 97.5% confidence intervals 
will be estimated. 
 
 
9.4.2 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
 
A logistic regression will be used including initial treatment (NRT vs NRT+CM) along with covariates for 
site, age, gender and HSI. Odds ratios, predicted probabilities of 12 week abstinence/reduction in 
smoking and 97.5% confidence intervals will be estimated. Multiple imputation by chained equations 
(MICE) will be used to impute missing abstinence outcomes. Baseline characteristics and abstinence 
outcomes assessed at other timepoints will be used in the missing data model. The difference between 
probabilities of 12 week abstinence/reduction between NRT and NRT+CM will be evaluated at the 0.025 
two-sided significance level (i.e. Bonferroni corrected for the 2 primary hypotheses).  
 
A similar analysis will be used for to evaluate the impact of the second randomization (i.e. switch vs 
intensify) in non-responders abstinence at 24 weeks. This analysis will only include participants who 
were non-responders to the initial treatment. For those non-responders initially randomized to NRT, 
switching refers to receiving VAR or bupropion in the second randomization while intensifying refers to 
receiving NRT+CM. For those non-responders initially randomized to NRT+CM, switching refers to 
receiving VAR or bupropion+CM in the second randomization while intensifying refers to receiving 
NRT+CM+. Logistic regression will include second stage treatment as well as covariates for site, age, 

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gender, HSI, reason for 12-week non-response (i.e. non-abstainer vs. loss to follow-up) and initial 
treatment group. Odds ratios, predicted probabilities of 24 week abstinence and 95% confidence 
intervals will be estimated. Multiple imputation by chained equations (MICE) will be used to impute 
missing abstinence outcomes. Baseline characteristics will be used in the missing data model. The 
difference between probabilities of 24 week abstinence between switching and intensifying will be 
evaluated at the 0.05 two-sided significance level. 
 
For secondary outcomes of CD4 cell count, HIV viral load and VACS index weighted linear mixed models 
will be used to estimate mean outcomes at 12 and 24 weeks for each of the treatment strategies. A 
random effect will be included for repeated measures and the analysis will include indicators for first 
and second randomization, time, the interactions of first/second randomization indicators with time as 
well as covariates for baseline outcome, site, age and gender. Inverse probability weighting will be used 
to account for non-responders being re-randomized. Least squares means and 95% confidence intervals 
will be estimated. Evaluation of initial treatment strategies at 12 and 24 weeks will be performed using 
linear mixed models. These analyses will include fixed effects for initial treatment, time and their 
interaction as well as covariates for baseline outcome, site, age and gender and a random effect for 
subject to accommodate repeated measures. Similar linear mixed models of only non-responders will be 
used to evaluate second stage treatment.  
 
 
9.4.3 SAFETY ANALYSES 
To assess safety of treatment interventions, we will describe adverse events by treatment group and 
compare by treatment group. We will additionally examine self-reported bothersome symptoms based 
on response to the HIV Symptom Index, numbers of hospitalizations and ED visits overall and by 
treatment group.  
9.4.4 BASELINE DESCRIPTIVE STATISTICS 
Randomization adequacy will be assessed by comparing the differences of baseline demographic and 
clinical characteristics among intervention groups.  
9.4.5 PLANNED INTERIM ANALYSES  
 
No interim looks are planned. 
 
9.4.6 SUB-GROUP ANALYSES 
To examine whether treatment differences vary among subgroups, we will conduct exploratory 
9.4.7 AND HYPOTHESIS GENERATING ANALYSES. WE WILL STUDY WHETHER TREATMENT 
EFFECTS DIFFER BY DEMOGRAPHIC AND CLINICAL CHARACTERISTICS COMMON 
AMONG PWH AND KNOWN TO BE ASSOCIATED WITH TOBACCO USE: DEPRESSION, 
ALCOHOL USE.TABULATION OF INDIVIDUAL PARTICIPANT DATA 
N/A 
9.4.8 EXPLORATORY ANALYSES 
 
Exploratory Analysis. We will determine the overall best strategy with regard to 24-week abstinence. 
There are four strategies to compare: 1) NRT followed by VAR or bupropion in non-responders; 2) NRT 
followed by NRT+CM in non-responders; 3) NRT+CM followed by VAR or bupropion+CM in non-
responders; 4) NRT+CM followed by NRT+CM+ in non-responders. Choosing the optimal strategy is an 
estimation rather than hypothesis testing problem. Weighted logistic regression will be used to estimate 
24-week abstinence rates for each of the strategies. Inverse probability weighting will account for non-

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responders being re-randomized and thus split in two groups as they will be underrepresented relative 
to responders. The analysis will include parameters for the initial randomization group as well as site, 
age, gender and HSI as baseline covariates. Predicted probabilities and 95% confidence intervals will be 
estimated for each of the strategies. The strategy with the highest predicted probability will be 
identified as the optimal strategy. 
 
We will additionally examine "dose response effects" and examine the impact of number of completed 
interventions sessions as measure of intensity of intervention on outcomes.7 
 
We will conduct exploratory analyses by subgroups (see 9.4.6). 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
10.1.1 INFORMED CONSENT PROCESS 
 
Where and When Consent Will Be Obtained 
For aims 1 and 2, patients will be consenting in person in the clinic where they have been recruited from 
or remotely. Due to social distancing requirements and safety protocols, if the situation requires, 
participant may be consented via phone or HIPAA compliant video conferencing with Zoom. Participants 
can either mail the signed consent or bring back a signed copy in person within two weeks of the phone 
call/video call or email it to research assistant. 
 
For aim 3, for the survey, clinicians, staff, clinical leadership, social workers, psychologists, and care 
coordinators will be located wherever they have access to email and the online REDCap survey. They will 
not be providing any health identifiers and thus there will be no need for HIPAA authorization. They will 
only need to provide consent prior to study activities. The consent document will be located on the very 
first page of the survey; participants will not be allowed to proceed unless they agree to the terms of 
consent.  
 
Waiting Period for Obtaining Consent 
Participants will have as much time as needed to thoroughly review the consent form. 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
 
Script for public service announcement (SUNY Downstate site only) 
MyChart script change (Yale site only) 
Recruitment letter change (Yale site only) 
Letters for participants lost to follow up (all sites) 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 

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Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. 
A verbal explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must be 
informed that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their records. 
The informed consent process will be conducted and documented in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigator, funding agency, and 
regulatory authorities.  If the study is prematurely terminated or suspended, the Principal Investigator 
(PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will 
provide the reason(s) for the termination or suspension.  Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor and IRB. 
 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 
biological samples in addition to the clinical information relating to participants. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict confidence. No 

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information concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB) or other regulatory agencies may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) 
and pharmacy records for the participants in this study. The clinical study site will permit access to such 
records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the Yale Coordinating Center. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems used by clinical sites and by the Yale Coordinating Center research staff will be secured and 
password protected. At the end of the study, all study databases will be de-identified and archived at 
the Yale Coordinating Center.  
 
Certificate of Confidentiality  
 
To further protect the privacy of study participants, a Certificate of Confidentiality will be issued by the 
National Institutes of Health (NIH).  This certificate protects identifiable research information from 
forced disclosure. It allows the investigator and others who have access to research records to refuse to 
disclose identifying information on research participation in any civil, criminal, administrative, legislative, 
or other proceeding, whether at the federal, state, or local level. By protecting researchers and 
institutions from being compelled to disclose information that would identify research participants, 
Certificates of Confidentiality help achieve the research objectives and promote participation in studies 
by helping assure confidentiality and privacy to participants. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at Yale University. After the study is completed, 
the de-identified, archived data will be transmitted to and stored at the Yale University, for use by other 
researchers including those outside of the study. Permission to transmit data to the Yale University will 
be included in the informed consent.  
 
eCO biological specimens will be collected but not stored. 
 
How PHI Will Be Protected from Improper Use or Disclosure 
Any identifiable information that is obtained in connection with this study will be disclosed only with 
participant 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. 

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Upon completion of the study, all computerized participant datasets will be coded and stored in a 
password-protected study computer, to which only the MPIs and study personnel will have access. Any 
paper files with participant 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. Any records containing PHI will be stored separately from coded 
data during storage, use, and transmission. Data will be collected on computers at study sites using 
REDCap. REDCap data will be uploaded live to a Yale maintained university server in encrypted fashion. 
This is a live connection; therefore, all data are immediately stored on the secure server. The server is 
backed up hourly. This system is compliant with HIPAA and regulations for the collection of ePHI. 
Computers are encrypted with PGP software.  
 
PHI Will Be Destroyed at the Earliest Opportunity Consistent with the Research 
Yes 
 
When and How PHI Will Be Destroyed 
Any paper files with participant 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. 
 
PHI Will Be Shared Yes 
 
Description of PHI that Will Be Shared 
Date of services such as clinic visit, counseling, lab results and measurements will be recorded and 
shared with participating research collaborators. 
 
Justification for Sharing PHI 
This information is necessary to provide a timeline and understanding of when these assessments took 
place, relative to the designated time points of the study. 
 
With Whom Directly PHI Will Be Shared 
Approved research personnel will have access to this information - Investigators, clinical research 
coordinators, biostatisticians. 
 
PHI Can Be Obtained By Members of the Research Team, 
Researchers at Mount Sinai, Researchers Outside Mount Sinai 
 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Medical Monitor 
Keith M Sigel, MD, PhD 
 
Mount Sinai Hospital  
  
1 Gustave L.  Levy Place, Box 
1087 NY, NY 10029 
 
212-825-7558 
 
keith.sigel@mssm.edu 
 

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10.1.6 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of 
individuals with the appropriate expertise, including experts in clinical trials for addiction and substance 
use disorders as well as experts in statistical analysis of clinical trials in substance use disorders. 
Members of the DSMB are independent from the study conduct and free of conflict of interest, or 
measures should be in place to minimize perceived conflict of interest.  The DSMB will meet at least 
semiannually to assess safety and efficacy data on each arm of the study. The DMSB will operate under 
the rules of an approved charter that will be written and reviewed at the organizational meeting of the 
DSMB. At this time, each data element that the DSMB needs to assess will be clearly defined. The DSMB 
will provide its input to NCI. 
 
 
10.1.7 CLINICAL MONITORING 
The Yale Coordinating Center will conduct monitoring visits to each study site on an annual basis. The 
MPIs, CM consultant, and Project Manager will meet with site PIs, interventionists, and research 
assistants at each site. The Project Manager will review the regulatory binder as well as inspect consent 
documents and protocol for correct versions. In addition, a random sample of participants’ data will be 
reviewed in detail to ensure appropriate data capture. The PIs and CM consultant will meet with the site 
PI and interventionists to review fidelity to the protocol, review study progress, and to make suggested 
changes as needed. These monitoring visits may be conducted either in-person or virtually.  
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 
Procedures for data collection, management, monitoring of quality, and analysis will include use of a 
computerized database system (REDCap) to monitor research activities, screening, 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 are planned. Monthly reports 

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will monitor accrual, randomization; data timeliness, quality, completeness, and overall event rates (e.g. 
abstinence). Error corrections will be documented. 
 
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. 
 
Anticipated Circumstances of Subject Withdrawal 
Participants may be withdrawn from the research without their consent if they are deemed ineligible for 
the study. Participants may also be withdrawn from the research if they have experienced serious or 
related adverse events. If any participant asks to withdraw from the study, he/she will be notified that 
medical record data collection will continue, but any interventional procedures may cease. If a 
participant asks for complete withdrawal from the study, he or she must do so by written notification to 
the site PI. 
 
Primary or Secondary Safety Endpoints 
The use of NRT involves minimal risk, and most risks are related to the use of the patch and discomfort 
at the site and difficulty sleeping. VAR's most common side effect is nausea at onset of use, which is 
generally manageable. The main risk with Bup is seizures, thus prescribing will be avoided in high risk 
individuals. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report 
form (eCRF) derived from source documents should be consistent with the data recorded on the source 
documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into REDCap, a 21 CFR Part 11-compliant data capture 
system provided by the Yale Coordinating Center>. The data system includes password protection and 
internal quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the source documents. 
 
10.1.9.2 STUDY RECORDS RETENTION  
 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harminosation (ICH) region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 

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formal discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform 
the investigator when these documents no longer need to be retained. 
 
10.1.10 
PROTOCOL DEVIATIONS  
 
 
Documenting Protocol Deviations 
 
Medications: 
If a participant does not receive the medications as part of their assigned treatment arm, this should be 
documented as a protocol deviation in REDCap. This may be entered once in the Protocol Deviation 
Form in the Baseline Forms, Week 12 Forms, Week 24 Forms, or Unscheduled Visit Forms.  
This may occur for various reasons: 1) participant declines a particular medication; 2) participant did not 
fill a prescription for any reason; 3) incorrect medication was prescribed.  
 
NRT: Participants should be prescribed both a long- and short-acting nicotine replacement therapy in 
Stage 1. If one or both were not acquired, then one protocol deviation should be submitted. 
VAR: If varenicline or bupropion was not acquired when a participant was randomized to either the VAR 
or VAR+CM arm in Stage 2, then one protocol deviation should be submitted.  
 
These deviations are not meant to be punitive in nature. Rather, we need a way to be able to track how 
often this is happening. (Medications actually taken will also be tracked via the Smoking Related 
Treatment Services Form) 
 
Incorrect CM draws: 
If participant is awarded an incorrect number of draws from the fishbowl, this needs to be documented 
as a protocol deviation. 
Some examples may be: 
a) 
Participant was awarded more than the maximum number of draws: 
Maximum is 9 draws for the NRT+CM intensified group 
Maximum is 5 draws for all other groups 
 
b) 
Participant was awarded draws, even if they reported smoking (even a puff) in the last 7 
days. 
Reminder: Smokerlyzer should ONLY be used to confirm a verbal report of no smoking in the 
past 7 days. Draws are then awarded if eCO <= 6ppm. 
 
c) 
Too many or too few draws per specific CM visit. 
 
We will not report medication deviations related to medication non-use and incorrect CM draws 
(described in the above sections) as individual events to the Mount Sinai IRB to limit administrative 
burden as they are not indicators of human subject risk. Instead, we will present these data as aggregate 
to our DSMB and in our annual report. 
 
It is the responsibility of the site Principal Investigator to use continuous vigilance to identify and report 
deviations within 5 working days of identification of the protocol deviation, or within 5 working days of 

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the scheduled protocol-required activity.  All deviations must be addressed in study source documents, 
reported the Yale Data Coordinating Center Protocol deviations must be sent to the reviewing 
Institutional Review Board (IRB) per their policies. The site investigator is responsible for knowing and 
adhering to the reviewing IRB requirements. Further details about the handling of protocol deviations 
will be included in the MOP. 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.  Data from this study may be requested from other researchers 7 years after the 
completion of the primary endpoint by contacting the lead PIs.    
 
As study results are obtained, Drs. Edelman and Bernstein will review findings, contribute to data 
analysis and interpretation, co-author manuscripts and presentations for scientific meetings, draft a 
proposed dissemination plan (e.g., determine target journals, author contribution, and order) and 
receive input from the investigative team on the proposed dissemination plan with a goal of identifying 
appropriate venues across the fields of HIV, substance use and tobacco focused research. Dr. Edelman 
also will be responsible for submission of annual progress reports and will be in communication with NIH 
project staff throughout the study. 
 
Consistent with NIH policy, we are planning to make the results and accomplishments of the study 
available to the research community and to the public at large. We will adhere to the NIH Grants Policy 
on “NIH Sharing Policies and Related Guidance on NIH-Funded Research Resources,” including the 
policies on “Sharing Clinical Trial Information,” including registration of our trial and reporting of all 
outcomes within ClinicalTrials.gov and work with institutional support at Yale University to ensure 
adherence to reporting timelines and ensure that consent procedures indicate this policy to inform 
potential participants. Results from the proposed research will be of interest to a wide range of 
audiences, including researchers in the fields of tobacco use and treatment, HIV, implementation 
science; service providers in HIV treatment settings; advocates for HIV treatment; and patients with HIV 
who smoke. 
 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 

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persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership in conjunction with the National Cancer Institute has established policies and procedures for 
all study group members to disclose all conflicts of interest and will establish a mechanism for the 
management of all reported dualities of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
 
N/A 
 

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10.3 ABBREVIATIONS 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CM 
Contingency Management 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
eCO 
Exhaled carbon monoxide 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act  
HIS 
Heaviness of Smoking Index 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MPI 
Multiple Principal Investigators 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
NRT 
Nicotine replacement therapy 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
PWH 
Persons with HIV 
QA 
Quality Assurance 
QC 
Quality Control 
RCT 
Randomized Controlled Trial 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
VAR 
varenicline 
VACS 
Veterans Aging Cohort Study 

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YCCI 
Yale Center for Clinical Investigation 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
1.1, 2.1, 2.2, 
3, 9.1 
12/22/22 
Change in primary and secondary 
outcome measures 
At the suggestion of the DSMB 
9.1, 9.2, 9.3, 
9.4 
12/22/22 
Change in statistical analysis due to 
changes in outcome measures and new 
reference added 
At the suggestion of the DSMB and 
biostatistician 
n/a 
12/22/22 
Extension of timeline to recruit into Year 
5 
To maximize recruitment, which 
was slowed during COVID-19 
surges. (Original recruitment 
timeline was through Year 4.) 
5.5 
12/22/22 
Addition of script for public service 
announcement to be shown in waiting 
room (SUNY Downstate site only) 
To reach patients in the waiting 
room so that they are aware of the 
study and can refer themselves for 
screening 
6.3 
12/22/22 
Sample size description to be deleted 
Biostatistician discovered that it is 
in the wrong section 
n/a 
12/22/22 
Changes made to the MyChart script and 
recruitment letter (Yale site only) 
Requested by the Yale IRB 
n/a 
12/22/22 
Letter to be sent to enrolled study 
participants who cannot be reached  
Some participants can no longer be 
reached by telephone due to 
numbers no longer in service 
4.1, 7.3 
12/22/22 
More specific language about texting 
participants in the study   
Requested by Mount Sinai IRB 
texting will no longer be done on 
Google Voice as it’s not HIPAA 
compliant and will now be using 
Zoom Phone 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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11 REFERENCES  
Include a list of relevant literature and citations for all publications referenced in the text of the protocol.  
Use a consistent, standard, modern format, which might be dependent upon the required format for the 
anticipated journal for publication (e.g., N Engl J Med, JAMA, etc.).  The preferred format is International 
Committee of Medical Journal Editors (ICMJE). Include citations to product information such as 
manufacturer’s IB, package insert, and device labeling.  
 
1. Pool ER, Dogar O, Lindsay RP, Weatherburn P, Siddiqi K. Interventions for tobacco use cessation in 
people living with HIV and AIDS. The Cochrane Library. 2016. 
2. Cahill K, Hartmann#Boyce J, Perera R. Incentives for smoking cessation. Cochrane Database of 
Systematic Reviews. 2015(5). 
3. Hughes JR, Keely JP, Niaura RS, Ossip-Klein DJ, Richmond RL, Swan GE. Measures of abstinence in 
clinical trials: issues and recommendations. Nicotine & Tobacco Res. 2003;5:13-25. 
4. West R, Hajek P, Stead L, Stapleton J. Outcome criteria in smoking cessation trials: proposal for a 
common standard. Addiction. 2005;100(3):299-303. 
5. Crivello ALJM, SA. Statistical Methodology for a SMART Design in the Development of Adaptive 
Treatment Strategies. (Tech. Rep. No. 07-82). . University Park, PA: The Pennsylvania State University, 
The Methodology Center.;2007. 
6. Carpenter, JR and Kenward MG (2007). Missing data in randomised controlled trials - a practical guide. 
Birmingham: National Institute for Health Research, Publication RM03/JH17/MK. Available 
at http://www.missingdata.org.uk 
7.. Pool ER, Dogar O, Lindsay RP, Weatherburn P, Siddiqi K. Interventions for tobacco use cessation in 
people living with HIV and AIDS. Cochrane Database Syst Rev. 2016(6):CD011120. 

APPROVAL
October 23, 2024
KEITH SIGEL
2128247558
keith.sigel@mssm.edu
Dear KEITH SIGEL:
On 10/22/2024 an Institutional Review Board of the Mount Sinai School of Medicine, in 
accordance with Mount Sinai’s Federal Wide Assurances (FWA#00005656, 
FWA#00005651) to the Department of Health and Human Services approved the 
following human subject research from 10/22/2024 to 10/21/2025 inclusive: 
Type of Review:
Modification and Continuing Review
Project Title:
R2S: A SMART Approach to Treating Tobacco Use Disorder 
in Persons Living with HIV
Investigator:
KEITH SIGEL
Project Information:
STUDY-19-01121-MODCR002
Funding Source: Name: Yale University School Of Medicine, 
Grant Office ID: 18-2805
MSHS System Sites:
St. Luke Hospital, Mount Sinai
IND, IDE, or HDE:
None
Documents Reviewed:
• 19-01121 Protocol Clean, Category: IRB Protocol;
• 19-01121 ProtocolTracked, Category: IRB Protocol;
• Advertisement 19-01121 SMARTTT_Pen_Mount Sinai.pdf, 
Category: Other;
• Chantix insert.pdf, Category: Drug Attachment;
• Documentation 19-01121 Cert HIC# 2000026332 
SMARTTT ICF Sinai Specific_12.9.2020_clean .docx.pdf, 
Category: Other;
• Documentation 19-01121 Certification HIC# 2000026332 
SMARTTT Reminder Slips Med ONLY.DOCX.pdf, 
Category: Other;
• Documentation 19-01121 Certification HIC# 2000026332 
SMARTTT Reminder Slips Medication CM.DOCX.pdf, 
Category: Other;
• Documentation 19-01121 CM Patient Education + 
Pharmacist Tips, Category: Other;

Page 2 of 8
• Documentation 19-01121 
MedicationCM_ReminderSlip_Sinai10.22.2020.docx, 
Category: Other;
• Documentation 19-01121 
MedicationOnly_ReminderSlip_Sinai10.22.2020.docx, 
Category: Other;
• Documentation 19-01121 Proposed added question in 
REDCap.docx, Category: Validated questionnaires / 
evaluation instruments;
• Documentation 19-01121 Template 
MedicationCM_ReminderSlip.pdf, Category: Other;
• Documentation 19-01121 Template 
MedicationOnly_ReminderSlip.pdf, Category: Other;
• Documentation 19-01121 Translated HIC# 2000026332  
SMARTTT Reminder Slips Medication CM.docx, Category: 
Other;
• Documentation 19-01121 Translated HIC# 2000026332 
SMARTTT Reminder Slips Medication ONLY.doc, Category: 
Other;
• Documentation 19-01121Certification HIC# 2000026332 
Tobacco Treatment HIV Study Mount Sinai.docx.pdf, 
Category: Other;
• DSMB Letter 19-09211 7.12.21, Category: Other;
• Flyer 19-01121 Smoking Flyer_03.10.2020_clean.pdf, 
Category: Recruitment Materials;
• Flyer 19-01121 Tobacco Treatment HIV General Template 
Flyer final.pdf, Category: Recruitment Materials;
• Flyer 19-01121 Tobacco Treatment HIV -Mount 
Sinai_finalpdf_6.30.21 edit.pdf, Category: Recruitment 
Materials;
• Flyer 19-01121 Translated Tobacco Treatment HIV Study 
Mount Sinai_CCedit_7.12.21.pdf, Category: Recruitment 
Materials;
• FW R2S - Moving sites from Ideate to RUTH.htm, Category: 
Other;
• HIPAA_waiver_authorization_SMARTTT_v3_AS.pdf, 
Category: Other;
• HRP-212 - FORM - Continuing Review Progress 
12.19.19_SINAI_FINAL.doc, Category: Other;
• HRP-388, Category: Other;
• HRP-410 - CHECKLIST - Waiver or Alteration of Consent 
Process 11.24.2020.docx, Category: Other;
• HRP-503 Full Version 19-01121 5.17.23, Category: Other;
• Implementation Survey SMARTTT_FINAL.docx, Category: 
Validated questionnaires / evaluation instruments;

Page 3 of 8
• Main ICF 19-01121 Translated SMARTTT ICF Sinai 
Specific_7.9.2021_clean.pdf, Category: Consent Form;
• Main ICF 19-01121_new 2022 template, Category: Consent 
Form;
• Memo regarding protocol changes 19-01121 7.12.21, 
Category: Other;
• nicorette insert.pdf, Category: Drug Attachment;
• nicotine lozenge insert.pdf, Category: Drug Attachment;
• nicotine patch insert.pdf, Category: Drug Attachment;
• Protocol 19-01121 Template-12.22.22_tracked, Category: 
Other;
• Protocol 19-01121 Template-SMARTTT_04-27-
2021_clean.docx, Category: Other;
• Research Info Sheet-Aim 3_second survey 08012024_Sinai 
specific.pdf, Category: Consent Form;
• Research Info Sheet-Aim 3_second survey 
08012024_template.pdf, Category: Consent Form;
• Sinai Specific Hard to Reach Participants Letter 19-01121 , 
Category: Recruitment Materials;
• Sinai Specific ICF 19-01121_new 2022 template, Category: 
Consent Form;
• Sinai Specific In-Person Screening Form_Sinai_Clean.pdf, 
Category: Recruitment Materials;
• Sinai Specific Patient Recruitment Letter_No 
Change_Sinai_Clean.pdf, Category: Recruitment Materials;
• Sinai Specific Sinai Smoking Flyer_07.28.2020_clean.pdf, 
Category: Recruitment Materials;
• Sinai Specific SMART English Phone 
Screener_Sinai_Clean.pdf, Category: Recruitment Materials;
• SMARTTT Video Content- Clinic Recruitment, Category: 
Recruitment Materials;
• Statement of Work - Mount Sinai - FINAL.docx, Category: 
Other;
• Study 19-01121 HRP235A Transition to 2022 Consent 
form_signed, Category: Other;
• Study 19-01121 HRP-235B Sinai Notification Plan to 2022 
consent form_signed, Category: Other;
• Template InPerson Screening Form 19-
01121_07.28.2020_clean.pdf, Category: Recruitment 
Materials;
• Template Patient Recruitment Letter 19-01121 
03.10.2020_clean.pdf, Category: Recruitment Materials;
• Template SMART English Phone 
Screener_03.10.2020_clean.docx.pdf, Category: Recruitment 
Materials;
• TSR modified FU.docx, Category: Other;

Page 4 of 8
• zyban bupropion insert.pdf, Category: Drug Attachment;
• The request for a waiver of informed consent was approved for the specified 
procedures described in the protocol.
The PHI for which access and use has been granted for this project [which are the 
minimum necessary] include the following
Identifiers:
Name
Date of Birth
Medical Number
Telephone Number
Dates of Service
Address/zipcode
Health Information:
For aim 1/2, electronic medical records, lab results, questionnaire answers, 
responses on measures, will all be used to provide data about the subjects.
Primary Care provider records:
- HIV/AIDs status, hepatitis infection status, sexually transmitted diseases, 
physical exam (height, weight, blood pressure), diagnosis and treatment of 
medical and psychiatric conditions, sexual practices, tobacco and alcohol use, use 
of illegal drugs, smoking status and habits, medication list, pregnancy status, 
language abilities, adverse events, side effects, transportation, time/costs travel to 
clinic.
Specialist provider records:
- HIV/AIDs status, hepatitis infection status, sexually transmitted diseases, 
physical exam (height, weight, blood pressure), diagnosis and treatment of 
medical and psychiatric conditions, sexual practices, tobacco and alcohol use, use 
of illegal drugs, smoking status and habits, medication list, adverse events, side 
effects, transportation, time/ costs travel to clinic

Page 5 of 8
Laboratory records and other test results:
-CD4 count, hepatitis infection status, sexually transmitted disease, viral load, 
creatinine, hemoglobin, WBC, eGFR, albumin, platelets, AST, ALT, Body-mass 
index.
Psychiatrist/therapy records:
- HIV/AIDs status, hepatitis infection status, sexually transmitted diseases, 
diagnosis and treatment of medical and
psychiatric conditions, sexual practices, tobacco and alcohol use, use of illegal 
drugs, smoking status and habits,
medication list, adverse events, side effects, transportation, time/costs travel to 
clinic
Phone call records:
- diagnosis and treatment of medical and psychiatric conditions, adverse events, 
side effects, transportation, time/
costs to travel to clinic
Demographics from electronic medical record:
-First name, last name, gender, date of birth, MRN, telephone number, 
employment status, insurance, income, self-identified gender identity, race, 
ethnicity, education, mailing address, proxies/alternate contacts, transportation, 
time/costs travel to clinic.
Requesting Waiver for Aim 3 of study procedures involving clinicians, staff and 
clinical leadership. Waiver is requested to perform pre and post trial surveys. 
Survey data will be collected in a de-identified fashion. No health identifiers will 
be collected. An information sheet will be used.

Page 6 of 8
• The request for a waiver of HIPAA authorization was approved. The PHI for 
which access and use has been granted for this project [which are the minimum 
necessary] include the following:
Identifiers:
Name
Date of Birth
Medical Number
Telephone Number
Dates of Service
Address/zipcode
Health Information:
For aim 1/2, electronic medical records, lab results, questionnaire answers, 
responses on measures, will all be used to provide data about the subjects.
Primary Care provider records:
- HIV/AIDs status, hepatitis infection status, sexually transmitted diseases, 
physical exam (height, weight, blood pressure), diagnosis and treatment of 
medical and psychiatric conditions, sexual practices, tobacco and alcohol use, use 
of illegal drugs, smoking status and habits, medication list, pregnancy status, 
language abilities, adverse events, side effects, transportation, time/costs travel to 
clinic.
Specialist provider records:
- HIV/AIDs status, hepatitis infection status, sexually transmitted diseases, 
physical exam (height, weight, blood pressure), diagnosis and treatment of 
medical and psychiatric conditions, sexual practices, tobacco and alcohol use, use 
of illegal drugs, smoking status and habits, medication list, adverse events, side 
effects, transportation, time/ costs travel to clinic
Laboratory records and other test results:
-CD4 count, hepatitis infection status, sexually transmitted disease, viral load, 
creatinine, hemoglobin, WBC, eGFR, albumin, platelets, AST, ALT, Body-mass 
index.
Psychiatrist/therapy records:
- HIV/AIDs status, hepatitis infection status, sexually transmitted diseases, 
diagnosis and treatment of medical and
psychiatric conditions, sexual practices, tobacco and alcohol use, use of illegal 
drugs, smoking status and habits,
medication list, adverse events, side effects, transportation, time/costs travel to 
clinic

Page 7 of 8
Phone call records:
- diagnosis and treatment of medical and psychiatric conditions, adverse events, 
side effects, transportation, time/
costs to travel to clinic
Demographics from electronic medical record:
-First name, last name, gender, date of birth, MRN, telephone number, 
employment status, insurance, income, self-identified gender identity, race, 
ethnicity, education, mailing address, proxies/alternate contacts, transportation, 
time/costs travel to clinic.
Requesting Waiver for Aim 3 of study procedures involving clinicians, staff and 
clinical leadership. Waiver is requested to perform pre and post trial surveys. 
Survey data will be collected in a de-identified fashion. No health identifiers will 
be collected. An information sheet will be used.
IRB approval requires that this research is conducted in full compliance with the 
requirements indicated in the PPHS/IRB Investigator Manual. Additionally, all required 
local committee approvals at each research affiliate site must be obtained prior to study 
initiation. 
It is imperative to recognize that IRB approval does not constitute or imply institutional 
support for the conduct of this research.  Further, IRB approval from Mount Sinai is 
provided with the understanding that the investigator and research team will strictly 
adhere to all laws and regulations governing research in the localities where the project is 
to be conducted.  
To access stamped consent forms, log into RUTH, search for your project in the IRB, 
Active tab, and click the Documents tab in the study workspace.
To avoid rejection of your manuscript by a journal and/or non-compliance with federal 
requirements, you must register and update your study on ClinicalTrials.gov via the 
ISMMS Office of Research Services (ORS) ticket Clinicaltrials.gov Assistance. For 
ICMJE studies, registration must occur prior to the first enrolled subject in your study 
and to meet federal requirements registration must be completed within 21 days after the 
first enrollment.  
As a courtesy reminder, in order to request continuing IRB approval or study closure, you 
are required to submit a Continuing/Final Review Progress Report and required 
attachments at least six weeks prior to your project’s expiration date. If IRB continuing 
review approval is not granted before the expiration date of 10/21/2025, IRB approval of 
this research expires on that date. There is no grace period beyond one year from the last 
approval date. It is your responsibility to submit your research protocol for continuing 
review.

Page 8 of 8
If your project qualified for an extended expedited expiration, and was given an approval 
period of more than one year, please note that the elimination of annual continuing 
reviews does not remove the responsibility of the PI/Research Team to monitor the 
ongoing conduct of the research. The rules as they apply to reporting new information, 
requesting modifications to the protocol or consent and making final reports have not 
changed. CITI refresher training for research staff must still be completed every three 
years, and financial conflicts of interest must be managed by the FCOI committee 
independent of the project approval period. In addition, any other changes by the PPHS, 
ISMMS, or federal or state regulations that affect projects, e.g. consent language changes 
or new policy, must still be implemented during the three-year period.
For questions, please contact the IRB staff member working on the project or the PPHS at 
212-824-8200.