Clinical Pharmacology of Electronic Cigarettes
Phase: NA
Conditions: Nicotine Dependence
Sponsor: University of California, San Francisco

Clinical Pharmacology of Electronic Cigarettes  
IRB# 15-15992 
 
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Clinical Pharmacology of 
Electronic Cigarettes 
R01 DA039264 
UCSF IRB #: 15-15992 
Clinical Trials.gov #: NCT02470754 
Manual of Procedures (MOP) 
NEAL BENOWITZ, M.D. (PI) 
DELIA DEMPSEY, M.D. (CO-I) 
MACIEJ GONIEWICZ, Pharm.D., Ph.D. (CO-I) 
PEYTON JACOB, Ph.D. (CO-I) 
GIDEON ST. HELEN, Ph.D. (CO-I) 
KEVIN WALTON, Ph.D. (NIDA Study Officer) 
March 2018 

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Table of Contents 
1 Table of Contents 
INVESTIGATORS, PERSONNEL, CONTACT INFORMATION ....................................................... 5 
BACKGROUND, GENERAL AIMS & STUDY DESIGN ..................................................................... 6 
2 
INTRODUCTION AND STUDY DESIGN ................................................................................... 7 
2.1 
RESEARCH QUESTION ........................................................................................................... 7 
2.2 
SPECIFIC AIMS .......................................................................................................................... 8 
2.2.1 Specific Aim #1 ........................................................................................................................... 8 
2.2.2 Specific Aim #2 ........................................................................................................................... 8 
2.2.3 Specific Aim #3 ........................................................................................................................... 9 
3 
STUDY DESIGN .............................................................................................................................. 9 
3.1 
DESIGN SUMMARY ................................................................................................................. 9 
3.2 
MAJOR STATISTICAL VARIABLES ...................................................................................... 9 
3.3 
PRIMARY RESEARCH SAMPLES ........................................................................................ 10 
3.4 
STUDY TIMELINE ................................................................................................................... 10 
3.5 
ELIGIBILITY ............................................................................................................................. 10 
3.5.1 Inclusion Criteria ...................................................................................................................... 11 
3.5.2 Exclusion Criteria ..................................................................................................................... 11 
3.5.3 Eligibility Determination ........................................................................................................ 13 
3.5.4 Reassessment of Eligibility ..................................................................................................... 13 
3.54a  Outside Orientation Visit Window .................................................................................. 13 
 
3.54b  30 Days Past Screening Visit ............................................................................................. 14 
4 
IDs & Assignment ......................................................................................................................... 14 
4.1.1 Study IDs ................................................................................................................................... 14 
4.1.2 Assignment Procedure ............................................................................................................ 15 
5 
PARTICIPANT WITHDRAWAL ................................................................................................ 16 
5.1.1 Dropout Definition .................................................................................................................. 16 
5.1.2 Dropout Compensation ........................................................................................................... 16 

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5.1.3 Lost to Follow-Up .................................................................................................................... 17 
 
5.13a  Contact Attempts ................................................................................................................ 17 
 
5.13b  Returning to Visit Procedures .......................................................................................... 18 
6 
VISIT SCHEDULE ......................................................................................................................... 18 
6.1.1 Visit Windows .......................................................................................................................... 18 
6.1.2 Study Days ................................................................................................................................ 19 
7 
RECRUITMENT METHODS ....................................................................................................... 19 
7.1 
PRELIMINARY REDCAP SCREENING .............................................................................. 19 
7.2 
CONFIDENTIAL PHONE SCREEN ..................................................................................... 20 
7.3 
EMAIL SCREENING PROCEDURES ................................................................................... 21 
8 
STUDY VISITS AND PROCEDURES ......................................................................................... 21 
8.1 
SCREENING VISIT .................................................................................................................. 21 
8.1.1 Consent ...................................................................................................................................... 21 
8.1.2 Urine Collection ....................................................................................................................... 22 
8.1.3 MILCOM ................................................................................................................................... 22 
8.1.4 Vital Assessment ...................................................................................................................... 23 
8.1.5 Screening Packet ....................................................................................................................... 23 
8.1.6 Saliva Collection ....................................................................................................................... 24 
8.1.7 End of Screening Visit ............................................................................................................. 24 
8.1.8 Post-Processing ......................................................................................................................... 24 
9 
PREPARATION FOR INPATIENT PORTION ......................................................................... 25 
9.1.1 Product Purchasing .................................................................................................................. 25 
9.1.2 5B Setup Paperwork ................................................................................................................ 25 
9.2 
ORIENTATION ........................................................................................................................ 27 
9.2.1 Product Assignment ................................................................................................................ 27 
9.2.2 Distribution of Study Products .............................................................................................. 27 
9.2.3 Product Use Diary .................................................................................................................... 28 
9.2.4 Urine Collection ....................................................................................................................... 28 
9.3 
STUDY BLOCK #1 ................................................................................................................... 28 

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9.3.1 Outpatient Days ....................................................................................................................... 28 
9.3.2 Admission & Inpatient Days .................................................................................................. 29 
9.4 
STUDY BLOCK #2 ................................................................................................................... 30 
9.4.1 Outpatient Days ....................................................................................................................... 30 
9.4.2 Admission & Inpatient Days .................................................................................................. 31 
9.5 
Summary of Standardized Puffing Protocols ...................................................................... 31 
9.6 
Product Weighing Procedures ............................................................................................... 31 
9.7 
PARTICIPANT COMPENSATION ....................................................................................... 35 
10 
ADVERSE EVENTS AND PROTOCOL DEVIATIONS ........................................................... 35 
10.1 
SAFETY MONITORING ......................................................................................................... 35 
10.2 
REPORTING ADVERSE EVENTS ......................................................................................... 36 
10.3 
PROTOCOL DEVIATIONS & VIOLATIONS ...................................................................... 36 
11 
DATA COLLECTION AND MANAGEMENT ......................................................................... 37 
11.1 
DATA COLLECTION FORMS ............................................................................................... 37 
12 
DUTIES AND RESPONSIBILITIES OF STAFF ......................................................................... 38 
12.1 
PRINCIPAL INVESTIGATOR ............................................................................................... 38 
12.2 
CO-PRINCIPAL INVESTIGATORS ...................................................................................... 38 
12.3 
STUDY PHYSICIAN ................................................................................................................ 38 
12.4 
PROJECT MANAGER ............................................................................................................. 38 
12.5 
CLINICAL RESEARCH COORDINATOR........................................................................... 38 
APPENDIX A: DATABASE GUIDE ...................................................................................................... 39 
APPENDIX B: STUDY POST-MORTEM .............................................................................................. 44 
 
 
 
 
 
 

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INVESTIGATORS, PERSONNEL, CONTACT INFORMATION 
 
Benowitz, Neal L., MD 
 
 
 
 
 
Principal Investigator 
 
 
 
 
 
 
 
 
neal.benowitz@ucsf.edu 
 
 
 
 
 
 
 
 
(415) 206-8324 
 
 
Dempsey, Delia A., MD 
 
 
 
 
Co-Investigator 
Study Physician  
 
 
 
 
 
 
 
 
delia.dempsey@ucsf.edu 
 
 
 
 
 
 
 
 
(415) 641-1465 
 
Goniewicz, Maciej, PhD, PharmD   
 
 
Co-Investigator 
 
 
 
 
 
 
 
 
maciej.goniewicz@roswellpark.org 
 
 
 
 
 
 
 
 
(716) 845-8541 
 
Jacob, Peyton, PhD   
 
 
 
 
Co-Investigator 
 
 
 
 
 
 
 
 
peyton.jacob@ucsf.edu 
 
 
 
 
 
 
 
 
(415) 282-9495 
 
St Helen, Gideon, PhD  
 
 
 
 
Co-Investigator 
 
 
 
 
 
 
 
 
gideon.sthelen@ucsf.edu 

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(415) 206-2687 
 
Nardone, Natalie, PhD 
 
 
 
 
 
Project Manager 
 
 
 
 
 
 
 
 
natalie.nardone@ucsf.edu 
 
 
 
 
 
 
 
 
(415) 514-1450 
 
Davis, Annalise                                                                                    Clinical Research 
Coordinator  
                                                                                                                  from May 2017-April 2018 
                                                                                                                  Annalise.davis@ucsf.edu 
 
Shahid, Marian  
 
 
 
 
              Clinical Research Coordinator   
                                                                                                                  from March 2015-April 
2017 
UCSF Tobacco Research Center 
 
 
 
tobaccocoord@ucsf.edu  
 
 
 
 
 
 
 
 
(415) 476-3555  
 
Tobin, Bernadette, RN 
 
 
 
 
Nurse Manager 
 
 
 
 
 
 
 
 
bernadette.tobin@ucsf.edu  
 
 
 
 
 
 
 
 
(415) 206-3317 
 
SFGH CTSI – 5B 
 
 
 
 
 
Front Desk 
 
 
 
 
 
 
 
 
5BScheduling@sfghgcrc.ucsf.edu 
 
 
 
 
 
 
 
 
(415) 206-8239 
 
BACKGROUND, GENERAL AIMS & STUDY DESIGN 
 
Electronic cigarettes (EC) are nicotine delivery devices that generate a nicotine-
containing aerosol which is inhaled by the user. EC are perceived by users to be useful 
in helping quitting smoking of conventional tobacco cigarettes (TC) as well as having a 
presumed lower risk of adverse health effects compared to TC, the potential for use in 
public places, reduced cost, and lack of the noxious clinging odors associated with TC 
use. The use of EC has dramatically grown in recent years and is currently estimated to 
be a billion dollar industry, with over 400 existing brands of EC and the three major U.S. 
tobacco companies now marketing their own brands. The FDA has announced the 
intention to regulate EC. 
  

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Key questions relevant to FDA regulation include the addictiveness and safety of EC. 
Many believe that electronic cigarette (EC) function as nicotine delivery devices in the 
same way as tobacco cigarettes (TC), and that EC will prove to be just as addictive as 
TC, but this may not be the case because of fundamental differences in the design and 
method of use of these products. For example, we hypothesize that systemic nicotine 
exposure will be lower with EC compared to TC; that despite lower nicotine intake EC 
users will experience similar reward and no greater withdrawal symptoms or craving 
compared to TC; and that dual EC/ TC users will not titrate their daily intake of nicotine 
in the same way that TC smokers of high- vs low-yield nicotine TC do. 
  
Our proposal specifically focuses on the areas that are thought to most closely relate to 
the addictive potential of EC, namely: (1) EC as nicotine delivery devices, covering 
issues of nicotine intake and pharmacokinetics, temporal patterns of use and titration of 
nicotine; and (2) subjective effects of EC use, including relationship of use to reward, 
withdrawal and craving. We will also examine aspects of safety of EC use (by 
assessment of cardiovascular and hormonal effects of use and of biomarkers of 
exposure to potentially toxic constituents) and explore the identification and validation 
of biomarkers that may be useful in distinguishing EC from TC use. Study participants 
will be dual users of TC and EC so that we may compare both modalities of use in 
experienced users in a within-participant design. 
  
The study will consist of two 1-week blocks (EC-only or TC-only conditions) with 4 
days of outpatient ad libitum product use followed by 3 days in a clinical research ward 
to include a single-use pharmacokinetic study, monitoring of product use, subjective 
assessments, blood and urine collections to assess biomarkers, and a 24-hour period of 
cardiovascular monitoring. Two additional days at the end of the 2nd block will assess 
similar measurements during a period of nicotine-product abstention. 
  
 
 
 
2 INTRODUCTION AND STUDY DESIGN 
2.1 RESEARCH QUESTION 
What are differences in the addictiveness and safety of electronic cigarette (EC) 
and tobacco (TC) use?  

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2.2 SPECIFIC AIMS 
2.2.1 Specific Aim #1 
To characterize nicotine delivery, systemic exposure and effects from 
Electronic Cigarettes. 
In dual EC/TC users instructed to use only EC or TC for a week at a time, 
we will address the following questions: 
• What fraction of nicotine inhaled from EC is retained in the body, and 
how is retention influenced by:  the type of device; the concentrations 
of nicotine, propylene glycol and glycerin in the e-liquid; the pH of 
the liquid; and the battery voltage? How does the time of peak 
nicotine concentration compare in EC vs TC use? 
• How does the amount of nicotine exhaled from EC use (important as 
a source of secondhand exposure to non-users) relate to the product 
characteristics? 
• What is the systemic exposure to nicotine from daily use of EC, and 
how is it influenced by the same product characteristics? How does 
exposure relate to the nicotine concentration of EC emissions as 
measured by smoking machine assays? 
• How does the daily intake of nicotine during ad libitum use compare 
for EC vs TC, and is there absolute or relative titration of nicotine 
intake when switching from one to the other? How much of the 
systemic nicotine dose from EC is absorbed via inhalation into the 
lungs and oropharynx vs swallowing into the gastrointestinal tract? 
• How do satisfaction, reward, craving and withdrawal symptoms 
compare for EC vs TC use? 
• How does the pattern of puffing compare for EC vs TC use? Are there 
similar patterns of regular vs clustered use within participants? 
2.2.2  Specific Aim #2 
To perform preliminary assessments of aspects of safety of Electronic 
Cigarette use. 
• What are the levels of exposure of tobacco smoke toxicants 
(particularly volatile organic compounds - VOCs) for dual use 
(baseline) vs EC-alone vs TC-alone vs no-product use? What is the 
relationship between propylene glycol (PG), glycerin and nicotine 
concentrations in the e-liquid, the EC emissions, and the urine 
mercapturic acid metabolite products of propylene oxide and 
acrolein, respectively? 

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• How do the cardiovascular effects (circadian heart rate, blood 
pressure and urinary catecholamine excretion) compare for use of EC-
alone vs TC-alone vs no-product? 
2.2.3  Specific Aim #3 
To validate biomarkers useful in distinguishing Electronic Cigarette use 
from Tobacco Cigarette use. 
• What is the sensitivity and specificity of the ratio of nicotelline to 
nicotine metabolites (cotinine or total nicotine equivalents) in urine 
when used to distinguish EC vs TC use? 
3 STUDY DESIGN 
3.1 DESIGN SUMMARY 
This study is an observational, crossover study that will evaluate the 
addictiveness and safety of electronic cigarettes (EC). It will focus on the areas 
that are thought to most closely relate to the addictive potential of EC, namely: 
(1) EC as nicotine delivery devices, covering issues of nicotine intake and 
pharmacokinetics, temporal patterns of use and titration of nicotine; and (2) 
subjective effects of EC use, including relationship of use to reward, withdrawal 
and craving. 
3.2 MAJOR STATISTICAL VARIABLES   
Predictor Variable List: nicotine intake and pharmacokinetics (24 hour plasma 
nicotine area under the curve (AUC) during ad lib and total nicotine equivalents 
(TNEs) in 24 hour urine samples), temporal patterns of use (average and 
variability of inter-puff or inter-cigarette interval and the fraction of total daily 
units consumed in each of four 4-hour intervals throughout the day), and 
titration of nicotine (ratios of 24 hour AUCs or 24 hour TNEs for EC/TC), levels 
of reward (CES), withdrawal (MNWS) and craving (QSU). 
Primary Outcome: concentrations of nicotine, cotinine, multiple nicotine 
metabolites in urine, the retention of nicotine, amount of nicotine exhaled, 
average daily nicotine intake, titration of nicotine intake and estimated 
swallowing vs inhalation of nicotine.  

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Refer to Page 3 of the Data Safety and Monitoring Plan for secondary and tertiary 
outcomes. 
3.3 PRIMARY RESEARCH SAMPLES  
Plasma: nicotine, cotinine, 3-Hydroxicotinine (3HC), IL-6, C-reactive protein, s-
ICAM, angiopoietin-2 and vascular endothelial growth factor (VEGF).  
Urine: nicotine, nicotine metabolites (nicotine equivalents), NNAL, 
catecholamines, mercapturic acid biomarkers of acrolein and propylene oxide, 
and other volatile organic compounds (VOCs), minor alkaloids (including 
anabasine, anatabine, and nicotelline), 8-iso-PHF alpha, 11-dehydro-TxB2.  
A detailed Schedule of Assessments outline number of samples and assays is 
located in the Crossover Study folder on the t-drive under Databases.  
3.4 STUDY TIMELINE 
• Application submitted to the Institutional Review Board (IRB): 3/19/2015 
• Approval date: 3/23/2015 
• Expiration date: 3/22/2018  
• Dates of enrollment: 12/7/2015-2/2/2018 
3.5 ELIGIBILITY 
Potential participants will express interest in participation by calling the UCSF 
Tobacco Research Center Recruitment Line, filling out the secure REDCap survey 
hyperlink from the Craigslist ad, or by emailing the UCSF Tobacco Research 
Center email address. Participants will be contacted to take part in a confidential 
phone screen or email screening to determine if they are eligible to come in for an 
in-person screening visit. At the in-person screening visit, participants will fill 
out case report forms (TC & EC use, medical history, etc.), the Clinical Research 
Coordinator (CRC) will take physiological measurements (blood pressure, 
height, weight, expired CO, etc.), and the participants will provide sample 
collections (urine and saliva). The participant’s study chart will be reviewed by 
the Study Physician in order to determine study eligibility. 
All individuals interested in participating and who meet the inclusion/exclusion 
criteria will be invited to be part of the study. Inclusion criteria are described 
below. 

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3.5.1   Inclusion Criteria 
• 
Healthy on the basis of medical history and limited physical examination.  
o Heart rate < 105 BPM*  
o Systolic Blood Pressure < 160 and > 90* 
o Diastolic Blood Pressure < 100 and > 50*  
*considered out of range if both machine and manual readings are above/below these 
thresholds 
o Body Mass Index ≤ 38.0 
• 
Current regular “dual” user of both EC and TC 
o Using same EC device at least 15 days out of the past 30 days 
o Nicotine strength of e-liquid ≥ 6 mg/mL, if using a 2nd or 3rd 
generation device, or willing to use a 6mg/mL strength e-liquid for 
the duration of the study 
o Conventional TC (≥ 5 CPD for past 30 days)  
o Carbon monoxide ≥ 5 ppm or per discretion of Principal Investigator  
o Saliva cotinine ≥ 50 ng/mL or urine cotinine via NicAlert 
• 
EC device is one of the most popular 1st, 2nd, or 3rd generation brands (with 
the exception of rebuildable atomizers) as determined at time of study 
commencement 
• 
Age: ≥  21 years old  
3.5.2   Exclusion Criteria 
• 
Medical 
o The following unstable medical conditions:  
 
Heart disease 
 
Uncontrolled hypertension 
 
Thyroid disease 
 
Diabetes 
 
Hepatitis B or C or Liver disease 
 
Glaucoma 
 
Prostatic hypertrophy 
• 
Psychiatric   
o Current or past schizophrenia, and/or current or past bipolar disorder 
o Adult onset ADHD (if being treated) 
o Participants with current or past depression and/or anxiety disorders 
will be reviewed by the Study Physician and considered for inclusion 

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o Psychiatric hospitalizations are not exclusionary, but study 
participation will be determined as per Study Physician’s approval 
• 
Drug/Alcohol Dependence 
o Alcohol or illicit drug dependence within the past 12 months with the 
exception of those who have recently completed an alcohol/drug 
treatment program 
o Positive toxicology test at the screening visit (THC okay) 
o Methadone replace therapy 
• 
Psychiatric Medications 
o Current regular use of any psychiatric medications with the exception 
of SSRIs and SNRIs and current evaluation by the Study Physician that 
the participant is otherwise healthy, stable, and able to participate.  
• 
 Medications 
o Use of medications that are inducers of nicotine metabolizing enzyme 
CYP2A6 (Example:  rifampicin, dexamethasone, phenobarbital, and 
other anticonvulsant drugs) 
o Use of medications for cardiovascular conditions including 
hypertension (Example: beta and alpha-blockers) 
• 
Other/Misc. Health Conditions 
o Oral thrush 
o Fainting 
o Untreated thyroid disease 
o Other “life threatening illnesses” as per Study Physician’s discretion 
• 
Pregnancy  
o Pregnancy (self-reported and urine pregnancy test) 
o Breastfeeding (determined by self-report) 
• 
Use of Other Tobacco Products (OTP) 
o Any of the following products in combination more than 15 times in 
the past month 
 
smokeless tobacco 
 
pipes  
 
cigars, cigarillos 
 
blunts, spliffs  
• 
Concurrent use of nicotine-containing medications (Example: nicotine 
patch, lozenge, gum) 
• 
Concurrent participation in another clinical trial. 

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• 
Inability to communicate in English. 
• 
Planning to quit smoking within the next 60 days  
 
3.5.3    Eligibility Determination 
After completion of in-person screening procedures, the CRC will complete an 
Eligibility Checklist which lists all inclusion/exclusion criteria and the 
participant’s status based on responses in the case report forms. The Project 
Manager and CRC will review the Eligibility Checklist after the saliva cotinine 
results are available. 
The Project Manager and CRC will refer to the Study Physician or Principle 
Investigator if the participant: 
• Currently takes any medications on schedule or as needed  
• Has current or past depression and/or anxiety disorders 
• Has any psychiatric hospitalizations in medical history 
The Study Physician will review the information and sign off on the Eligibility 
Checklist or indicate that the participant is ineligible. If none of the above 
conditions are present, the CRC and Project Manager will sign off on Eligibility 
Checklist without Study Physician review.   
The participant will be notified of eligibility via phone or email after this 
review. 
3.5.4 Reassessment of Eligibility 
Eligibility may need to be reassessed if the following conditions occur: the 
orientation visit is out of window (e.g. 90 days past from screening visit), and/or 
30 days have passed since the time of the screening visit.  
3.54a  Outside Orientation Visit Window  
If the participant is outside of their orientation visit window of 90 days, the 
screening visit will be repeated. The original screening visit data will remain 
in the study chart, however it will not be used for analysis. The participant 
will repeat all visit procedures, forms, and provide a saliva sample to be re-
sent for analysis.  

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3.54b  30 Days Past Screening Visit  
If 30 days have passed since the screening visit, in order to ensure that no 
significant changes have occurred in a participant’s current medical status 
and smoking/vaping habits, the CRC will review some eligibility items. This 
will occur if the participant is more than 30 days, but less than 90 days 
outside of their screening visit window. The CRC will ask the following over 
the phone:  
• if there are any new medications 
• if they have seen a physician for any medical/psychological  
reason  
• if they are still using their e-cigarettes and tobacco cigarettes as 
indicated at the in-person screening visit  
If any significant changes have occurred, the CRC and Project Manager will 
meet to discuss and complete another Eligibility Checklist based on current 
participant responses. 
4 IDs & Assignment 
4.1.1 Study IDs 
At the start of the phone screen, participants will automatically be assigned a 
REDCap ID which will start at the number “1” and be in sequence of the order of 
participants screened. The email screen database will also be numbered 
sequentially by participant, starting at 1000. These two REDCap databases will 
later be merged to become one database containing all entries for those screened 
by phone and by email for this study. Participants will be assigned a REDCap ID 
regardless of their eligibility status.   
Participants who are eligible for an in-person screening visit will be assigned a 
unique Study ID upon consent to participate in the study. This Study ID will 
begin with the “6885” to refer to the CTSI-5B study number, which is how the 
study is referred to at the research ward. These numbers will be followed 
sequentially starting from 001. For example, the first participant enrolled will 
have a Study ID of 6885-001.  

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The Screening Visit Log will keep track the REDCap IDs, and Study IDs (if 
consented). This log will be maintained as a hard and electronic copy.  
4.1.2 Assignment Procedure 
The participant will be assigned to one of two groups: 
1) Electronic Cigarette (EC) only for Study Block #1 and Tobacco Cigarette 
(TC) only for Study Block #2. 
OR 
2) Tobacco Cigarette (TC) only for Study Block #1 and Electronic Cigarette 
(EC) only for Study Block #2. 
The participant will not be considered for assignment until it has been verified 
that he/she is eligible and the Eligibility Checklist has been signed. The 
participant will be tentatively assigned to one of the two groups when he/she is 
scheduled for an orientation visit.  
The CRC will purchase both tobacco and e-cigarette products in case the 
assignment changes. The final product assignment will take place at the 
orientation visit. The CRC will refer to the “6885 Eligible Participants Log,” input 
the participant’s initials, product assignment, and date he/she is assigned to that 
condition. Assignment does not necessarily reflect the sequence of the 
participant’s consent in the study, but rather when he/she is booked for the start 
of orientation. That time course will vary based upon participant, CRC and CTSI 
availability.  
If a participant drops out or is lost to follow-up (LTFU) during the study, he/she 
will not be replaced. The assignment schedule will continue as assigned, and the 
PI can decide to enroll additional participants to compensate for non-completers.  
Study group assignment will be based on the following Assignment Schedule: 
(NOTE: Participant ID in the table below may or may not correspond to 
Participant Study ID) 

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5 PARTICIPANT WITHDRAWAL 
5.1.1 Dropout Definition 
If a participant declares he/she is no longer interested in completing the study, 
he/she will be considered a “dropout.” Once given “dropout” status, the 
participant can no longer contribute to the study.  
5.1.2 Dropout Compensation 
If participant decides to stop participating in the study prior to starting the 
inpatient portion of the study, he/she will only receive compensation for the 
Screening Visit ($30) and no compensation will be given for the inpatient portion. 
If a participant decides to drop out during the inpatient study, compensation will 
be as follows: 
• Inpatient admission Study Block #1 

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o Day 1 - $200 
o Day 2 - $400 
o Day 3 - $600 
If the participant does not complete the early morning procedures on the 
morning of Day 4 before discharge, he/she will still be compensated $600 for 
completion of the full study block   
• Inpatient admission Study Block #2: 
(amounts would also include + $600 for completion of Study Block #1)  
o Day 1 - $180  
o Day 2 - $360  
o Day 3 - $540  
o Day 4 - $720 
o Day 5 – N/A, participant would get full $900 +$500 bonus 
“Day” indicates a full 24 hours of procedures. If the participant leaves in less 
than 24 hours of that day, the CRC and Project Manager will discuss providing 
compensation for a partial amount.  
5.1.3 Lost to Follow-Up 
If a participant is unable to be contacted and does not respond to calls from the 
Clinical Research Coordinator, he/she will be considered “lost to follow-up” 
(LTFU). If a participant is considered LTFU, every effort will be made to contact 
him/her. 
5.13a  Contact Attempts 
After three unsuccessful phone and email contact attempts, a letter of 
intent to contact will be mailed to the participant’s home address. This 
letter will inform the participant that they will be formally withdrawn 
from the study by the date that is 90 days past the last point of contact.  It 
will also include details on the remaining study compensation available if 
procedures were continued. If the participant fails to contact the CRC after 
this outreach, and 90 days have passed since last communication, he/she 
will be considered “lost to follow-up”. No further outreach will be 
conducted. Once given “LTFU” status, the participant can no longer 
contribute to the study.  

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5.13b  Returning to Visit Procedures 
If a formerly lost participant returns, before starting the inpatient portion 
of the study, the reassessment of eligibility steps outlined in Section 3.5.4 
of this manual will be followed. If the participant is LTFU during some 
point in his/her inpatient portion, there will not be the option to repeat 
this.  
6 VISIT SCHEDULE  
The Study Visit chart below describes the schedule of visits and procedures.  
 
6.1.1 Visit Windows 
Table 1 describes the schedule of visits in relation to the start point of the 
Phone/Email Screen. Ideally, participant assessments will fall within the 
designated windows.  
   
  Table 1 
Assessment Point 
Maximum Time 
allowed from  
Phone/Email Screen 
Maximum Time 
allowed from 
Screening Visit 

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Phone/Email Screen 
 
 
Screening Visit 
30 days 
 
Orientation 
120 days 
90 days 
Every effort should be made to enroll and run eligible participants. Thus, if 
participants are outside of their screening visit or orientation visit windows, 
reassessment of eligibility will occur as described in Section 3.5.4.  
6.1.2 Study Days 
Due to CTSI closure on weekends, participants must come in for their 
Orientation Visit on a Thursday morning. Orientation Visits conducted on 
Thursday mornings allow for the first and second inpatient admissions to take 
place on Monday mornings without the issue of weekend closures, and allow for 
study completion on Fridays.  
7 RECRUITMENT METHODS 
Our methods of recruitment will be as follows: 
• 
Postings to craigslist (paid and free sections)   
• 
Flyers posted in mostly institutional settings (colleges, career centers, 
churches) and left at vape and smoke shops  
• 
Newspaper ads (typically Bay Guardian, SF Weekly, East Bay Express) 
• 
Blogs, google+ and social networking sites 
• 
Contact of prior callers or study participants who have given permission for 
re-contact as documented either in the consent form for the prior study or in 
our phone screening database. 
Individuals who respond to recruitment postings/flyers will be screened by phone 
or email to determine potential eligibility. Based on this initial assessment they 
may be asked to come to the UCSF Tobacco Research Center for an in-person 
screening visit. Additionally, participants from previous studies at the UCSF 
Tobacco Research Center, who appear to be eligible for the study will be re-
contacted and asked if they are interested in participating. 
7.1 PRELIMINARY REDCAP SCREENING 
Individuals who see the ad through Craigslist will be prompted to click on a 
hyperlink which will lead them to a preliminary screen on REDCap, or email the 
UCSF Tobacco Coordinator address for more information.  

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The preliminary REDCap screen (“UCSF Tobacco Research Email Screen”) is a 
short survey in which the participants provide the following information: 
• Contact information 
• E-Cigarette/Tobacco Cigarette product use 
• Prescription Medication Use 
• Exclusionary medical conditions 
This REDCap survey is programmed to generate a report of eligible participants. 
For example, a parameter is set for cigarettes per day to only include participants 
who smoke ≥5 cpd in the report. The information for eligible participants will be 
exported weekly from REDCap into an Excel sheet.  The CRC will use this 
information to call only valid prospects, and schedule these participants to come 
in for an in-person screening visit.  
7.2 CONFIDENTIAL PHONE SCREEN 
At the beginning of this study, a Confidential Phone Screen was used before 
migrating exclusively to the REDCap Screening. The CRC will call eligible 
individuals, as described above, to conduct a thorough Confidential Phone 
Screen. Additionally, individuals who call the UCSF Tobacco Research Center 
Recruitment Line directly will undergo the phone screen. Data generated from 
this phone screen will be entered into REDCap. The CRC will explain that 
questions will be asked regarding the individual’s tobacco product use and 
health history, and that the expected length of the screen is approximately 10 
minutes.  
Procedures for the Confidential Phone Screen include the following:  
• The CRC will record the participant’s personal information in a secure 
Access Database. This includes their name, phone number, email address, 
date of birth, and address. 
• After completing the Access Database fields, the CRC will open REDCap 
and start a new entry. The REDCap ID number that populates will be 
copied into the Access Database to connect the personal information to the 
screening data. No identifiers are recorded in REDCap.   
• The CRC will administer a series of eligibility questions, collected in the 
Phone Screen REDCap form (“E-Cigarette R01 & Flavors Study Screen”).   
• The CRC will determine if the participant is eligible to attend an in-person 
screening visit based on the inclusion/exclusion criteria. 

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If the participant is ineligible during the phone screen, the CRC may choose to 
end the phone screen when appropriate. In the event of an eligible participant, an 
in-person screening will be scheduled immediately. 
7.3 EMAIL SCREENING PROCEDURES 
Individuals who email the UCSF Tobacco Coordinator email address for more 
information about the study will receive an email asking them to complete a 
survey via REDCap. This survey will serve to determine their eligibility to attend 
an in-person screening visit.  
Procedures for the email screen include the following: 
• The CRC will respond and ask the participants to complete the REDCap 
Email Screening Survey (“Crossover Study Email Screen”). The REDCap 
Email Screening Survey has all of the same questions as the Confidential 
Phone Screen, but is in a survey format that the participants will fill out 
themselves. Additionally, it contains a field for email addresses, so the CRC 
can connect participants via their email addresses to their responses.   
• A report in the REDCap Database will generate a list of eligible 
participants.  
• If eligible, the CRC will call the participant to schedule them to come in for 
an in-person screening. 
8 STUDY VISITS AND PROCEDURES 
8.1 SCREENING VISIT 
Participants will undergo a 1-2 hour in-person screening visit to determine study 
eligibility. During this visit, participants will complete a basic physical 
assessment: height, weight, heart rate, blood pressure, expired carbon monoxide, 
urine toxicology test, and pregnancy test (if applicable), saliva collection, a 
MILCOM, and a Screening Packet containing questions regarding medical 
history and product use. Photographs of the participants’ e-cigarette and e-liquid 
will be taken. 
The schedule of procedures for the screening visit will occur in the order as 
follows: 
8.1.1 Consent 
Upon initiation of the screening visit, the CRC will greet the participant and ask 
to see a valid form of identification to verify their age.  Next, the CRC will ask 

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him/her to read the first line of the consent form aloud to confirm literacy. The 
CRC will instruct the participant to read each page of the consent document and 
initial at the bottom of each page indicating content understanding. The 
participant will be asked to refrain from signing the consent form until the CRC 
returns to discuss the consent form and answer any questions the participant 
may have regarding the study. The CRC will leave the room for approximately 
10 minutes to allow the participant an adequate amount of time to read the 
consent form. The CRC will return, answer any questions, and present a brief 
PowerPoint presentation highlighting important aspects of the consent 
document. Consent will be obtained via participant and CRC signatures at the 
conclusion of the presentation. Two copies of the consent document will be 
signed and dated by both the participant and the CRC. The CRC should retain 
the initialed copy and the second copy, and the third copy will be given to the 
participant for their records. Additionally, the participant will be asked to review 
and sign two HIPAA forms, and a third copy will be given to the participant for 
their records.  The participant will also be asked to read a copy of the Bill of 
Rights to ensure that the participant is aware of his/her rights in participating in 
a research study. 
8.1.2 Urine Collection 
After consent, the participant will be asked to provide a urine collection to test 
for drug use and pregnancy testing (if female).  
If the participant has a positive toxicology screen (marijuana is okay), he/she will 
be dismissed and given the option to rescreen within 30 days. 
The steps for the urine collection toxicology and pregnancy screenings are found 
in the “Urine Toxicology Screen SOP” and “Pregnancy Screen SOP.” 
8.1.3 MILCOM  
After confirming a negative toxicology screen and negative pregnancy screen, 
the participant will be asked to complete the MILCOM, a comprehensive Health 
History Questionnaire.  
• Follow-up is required if any symptoms are endorsed on the MILCOM in 
the following Sections:  
o Additional Illness or Problems 
o Head and Neck 
o Respiratory  
o Cardiovascular 
o Musculoskeletal  

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o Skin 
o Neurological 
o Mood 
The CRC will follow up with the participant asking: 
o How often and when was the last time you experienced these 
symptoms?  
o Do you ever take medication for this? If so, how often?  
Notes on the MILCOM follow-up will be recorded in empty space on the form.  
8.1.4 Vital Assessment 
The following physiological measures will be assessed: 
• Height and Weight 
• Blood pressure and heart rate 
• Expired carbon monoxide (CO) 
Steps for these assessments are found in the “Measuring Basic Vitals SOP” and 
“Measuring Expired CO Levels SOP.” 
If the participant’s blood pressure is out of range, it will be re-tested at the end of 
the visit manually, following the saliva collection. If it is still out of range, they 
will be considered ineligible. If the participant’s expired CO levels are not ≥ 5 
ppm, CRC may proceed with screening visit and the PI will use their discretion 
to determine eligibility.  
8.1.5 Screening Packet 
The screening packet will then be administered. It is broken into four main parts: 
• Section 1: Personal Data Form  
o This section contains the participant’s contact information as well as 
an Emergency Contact. 
• Section 2: Demographics  
o This section contains information regarding the participant’s gender, 
age, ethnicity, race, and education. 
• Section 3: Tobacco Product Use  
o This section contains information regarding participant’s use of 
nicotine replacement therapy, tobacco and e-cigarette product use, 
and drug/alcohol use.  
• Section 4: Medical History  

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o This section contains information regarding the participant’s medical 
history, including exclusionary medical and psychiatric conditions.  
o If any symptoms are endorsed on the Medical History in Section 4 
the CRC will follow up with the participant asking: 
 How often and when was the last time you experienced these 
symptoms?  
 Do you ever take medication for this? If so, how often?  
Notes on the Medical History follow-up will be recorded at the bottom of the last 
page of the form.   
The steps for administering and reviewing questionnaires are found in the 
“Administering Forms and Questionnaires SOP.” 
8.1.6 Saliva Collection 
After the participant completes the Screening Packet, he/she will be asked to 
provide a saliva collection. The steps for the saliva collection are found in the 
“Saliva Collection SOP.” 
8.1.7 End of Screening Visit 
At the end of the screening visit, the participant will be asked to fill out a 
“Certificate of Participation” in order to receive compensation for the screening 
visit. The participant will be dismissed and the CRC will inform him/her that 
he/she will be contacted in 1-2 weeks with eligibility results from the screening 
visit.  
8.1.8 Post-Processing  
The participant’s urine will be discarded and the CRC will store the participant’s 
saliva in the freezer at the UCSF Tobacco Research Center lab. The saliva samples 
will be labeled with the Study ID and transferred to the Benowitz Lab at the end 
of the day on Friday afternoons. The CRC will complete a Screening Log on the 
Shared Lab Drive filling in information on the samples dropped off. Cotinine 
results will be expected the following Tuesday.  
The MILCOM will remain a source document and will not be entered into an 
electronic database. The CRC will complete the Screening Visit Log (#6885 
Participant Log & Tallies) and enter data from the Screening Packet into the 
“Crossover Screening Packet” REDCap database. Data entry should occur within 
48 hours of the screening visit.  

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The CRC will submit the participant’s check request after confirming the 
participant’s smoking/vaping status (COT ≥ 50 ng/mL).  If the participant’s 
cotinine is <50 ng/ml, they will not be compensated for their screening visit. 
9 PREPARATION FOR INPATIENT PORTION 
9.1.1 Product Purchasing 
The CRC will purchase the participant’s EC or TC products from local vape or 
smoke shops using a petty cash fund. The CRC will purchase enough products to 
be used for the participant’s 4 outpatient days, inpatient study days, and for lab 
analysis. In order to determine total TC products, the CRC will refer to the 
Screening Packet, Section 3: Tobacco Smoking History, question #8 for cigarettes 
per day. In order to determine total EC products, the CRC will refer to Screening 
Packet, Section 3: E-Cigarette History, questions #4 and #6 in order to get a 
proper approximation of how much e-liquid the participant uses per day. Refer 
to Section 9.2.2. for description of the calculations.  
9.1.2 5B Setup Paperwork 
After study dates have been confirmed with the participant and the research 
ward, an admission request will be submitted via secure email to the research 
ward. The CRC will then prepare CTSI-5B Set-up paperwork for the admissions.  
The set-up paperwork consists of the following: 
Coversheet 
• The coversheet contains general information regarding the study 
and supplies needed. 
• CRC will place a label with the participant’s name and study ID, 
and edit the admission and set-up drop-off dates. 
Consent Form and HIPAA 
• An original signed copy of the consent form and HIPAA from the 
Screening Visit will be included in the set-up. 
Nurses Flow Sheet 
• The Nurses Flow Sheet contains study procedures and time points 
for each day of the inpatient admission. 
• CRC will update this form with participant’s TC and EC product 
brands. 

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MD Orders 
• The MD Orders are pre-signed by the Study Physician that will 
conduct the physical during the admissions.  
• CRC will write in the admission date and pencil in the participant’s 
name on the top right corner.  
Admit PE 
• The Admit PE will be filled out by the Study Physician as they 
perform the history and physical. 
• CRC will pencil in participant’s name in the top right corner. 
Adverse Event Form 
• The Adverse Event form is included in the set-up should any 
adverse events occur during the course of the study.  
• CRC will change the study ID. 
                      Other Study Forms 
• Caffeine Log is included to track participants’ inpatient caffeine 
intake 
• Study Questionnaires included are the following: Questionnaire of 
Smoking Urges (QSU), modified for E-Cigarettes Cigarette 
Evaluation Scale (mCES), Positive and Negative Affect Scale 
(PANAS), and Minnesota Behavioral Scale (MNWS) 
• The Outpatient Withdrawal Form is used to describe symptoms 
that participants felt over the outpatient study period (Thursday-
Sunday).  The Withdrawal Form asks participants to rate their 
symptoms on a scale of 1-5.  For participants who rated any given 
withdrawal symptom as being a 3 or 4, the CRC followed up with 
the participant to ask which outpatient days they had those 
symptoms, and if any day was more intense than any other.  These 
notes were recorded next to the corresponding item on the form.  
• The 48-Hour Product Use Form was intended to be used to track 
outpatient product use in cases where participants did not fill out 
their product diaries over the outpatient period.  This form was 
kept on hand, but never used for any of the participants. 
• The End of Study Questionnaire was given to participants on the 
final day of the study in the second block, and asked about their 
compliance with study procedures during the study.  

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9.2 ORIENTATION 
Participants will attend an Orientation Visit on a Thursday, to begin their 
Outpatient Days in Study Block #1. This visit will last approximately 1 hour. 
During the Orientation Visit, study procedures will be described in detail again. 
The following will take place: 
9.2.1 Product Assignment 
The CRC will input the participant’s initials, product assignment, and date 
he/she is assigned to that condition into the “6885 Eligible Participants Log”.  
Product assignment procedures are described in Section 4.1.2. 
9.2.2 Distribution of Study Products 
Participants will be given EC or TC products (based on assignment schedule) to 
use for the 4 outpatient days prior to their admission to the CTSI-5B research 
ward. Before distribution, the CRC will weigh all of the products.  
For the 1st generation EC users, the EC device as well as the cartridges (if 
applicable) will be provided in the participant’s preferred flavor.  For 2nd 
generation, we will only provide the e-liquid vials.  In the case of multiple e-
liquid vials or cartridges, each vial/cartridge will be numbered with a label or via 
a sharpie pen before weighing.   
 The amount of devices or cartridges to provide will be estimated using the 
participant’s self- reported daily product usage on their screening packet.  Light 
to medium users will be given 1 vial or 3 cartridges to use over the outpatient 
period, and 1 vial or 3 cartridges will be purchased for their use during the 
inpatient period.  Heavier users will be given 2 vials or 5 cartridges to use over 
the outpatient period, and 2 vials or 5 cartridges will be purchased for their use 
during the inpatient period.  Before distributing any of the devices/cartridges or 
e-liquid vials, they will be labeled with a sharpie and this weight will be 
recorded on the center of the Product under “Ad Lib Use”.  The weight of that 
distributed e-liquid or cartridge after the participant’s use upon collection the 
following day can be found below the Ad Lib Use section under “Returned 
Products”.  
For the TC products, the number of cigarette packs provided will be determined 
by  the participant’s self-reported cigarettes per day on their Screening Packet, 
plus additional cigarettes to account for their exclusive use of one product.  The 
amount to purchase for both outpatient and inpatient will be calculated as: 
(cigarettes per day *7) + 1 pack, rounded to nearest pack.  The participants will be 
asked to collect their cigarette butts during their outpatient and inpatient study 

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days.  These butts will be collected and weighed.  The weights for the cigarette 
butts can be found on the TC Product Weights form.   
Participants will sign a product accountability form and be instructed to return 
all empty and unused products at the end of their outpatient period.    
9.2.3 Product Use Diary 
Participants will be asked to keep track of their product use during their 
outpatient days. Instructions for using the TimeJot app or paper diary will be 
reviewed at the Orientation Visit. 
As the TimeJot app is not compatible with an Android phone, participants who 
own an Android will use a paper diary.  On the paper diary, they will record 
their smoking start and end time, and how many puffs they take.  At the end of 
each outpatient day, the participant will take a picture of the paper diary and 
email it to the CRC. 
For the TimeJot app, participants will be instructed to select a pre-programmed 
button on the TimeJot app that records the participants’ smoking/vaping 
sessions. Participants will select the “Start” button when they begin a 
smoking/vaping session and a “Stop” button when they end. The information 
recorded in the TimeJot app is the date and duration of the sessions in seconds. 
Participants will email the final report to the secure UCSF Tobacco Coordinator 
email address at the end of the day, after their last vaping/smoking sessions.  
9.2.4 Urine Collection 
Participants will provide a urine collection to be tested for nicotine by-products. 
This urine collection will amount to 40mL. The CRC will adjust the urine pH, 
label, and store the urine in the UCSF Tobacco Research Center lab. The steps for 
adjusting the urine pH are found in the “Adjusting Urine pH SOP.” 
9.3 STUDY BLOCK #1 
9.3.1 Outpatient Days 
After the Orientation Visit, participants will begin their 4 outpatient days and use 
the product assigned at randomization. They will track their product use with 
the TimeJot app or paper diary, recording every time they start/stop a TC or EC 
session. After they have completed their use for the day, they will email the 
summary report to the CRC. If participants have not emailed their summaries by 
the following morning, the CRC will send them a reminder email. 

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9.3.2 Admission & Inpatient Days 
After the 4 outpatient days, participants will check into the San Francisco 
General Hospital Clinical Research Center on the morning of Study Block #1, Day 
#5 at approximately 7am. As required for all hospital admissions, participants 
will have a medical history and physical examination conducted by the Study 
Physician. 
On Day #5, the following will occur: 
• A plastic catheter (thin flexible tube) will be inserted into a vein on the 
participant’s forearms (this will be used to withdraw multiple blood samples 
and will be kept in place for about 10 hours). The participant will be given a 
light breakfast and, if he/she normally drinks caffeinated beverages, he/she 
will be allowed a cup of his/her usual beverage (coffee or tea).  
• Between 8:50-9:00am (depending on the assigned study product), the 
participant will be asked to smoke a commercial cigarette or e-cigarette 
device and to take puffs only at times signaled by the voice recorder or 
research team.  
o If this is an e-cigarette device the puffs will be directed as follows: 
taking one puff every 30 seconds for a total of 15 puffs on 1st 
generation devices and 10 puffs on 2nd/3rd generation devices.  
o If this is a tobacco cigarette, puffs will be directed as follows: taking 
one puff every 30 seconds until cigarette is consumed.  
• After each puff, we will capture the smoke the participant breathes out by 
asking him/her to exhale into a sterile polypropylene mouthpiece which is 
connected to 3 gas traps. The gas traps are connected in series (i.e. in a line) 
and contain diluted hydrochloric acid or a solution containing citric acid, 
sodium phosphate, and ascorbic acid. A vacuum pump connected to the traps 
will suck the exhaled smoke into the traps. There will be NO contact between 
the participant’s mouth or body with the diluted acidic solution in the gas 
traps. This step will allow us to compute the dose of nicotine taken in from 
the cigarette during the standardized session.  
• The participant will not be allowed to smoke again until 4 hours later, at 
which time he/she will be given his/her usual TC or EC and allowed to smoke 
it as he/she wishes.  
• Blood samples, about one teaspoon each, will be withdrawn just before 
smoking, and after the standardized session. Then during the 4-hour 
abstinence period, blood draws will take place at 2, 5, 15, 30, 45, 60, 90, 120, 
180, and 240 minutes.  

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• The participant will also be asked to fill out several Questionnaires about 
his/her smoking experience before and after smoking the TC/EC and during 
the 4 hours when he/she is not smoking.  
• The participant will not be allowed to doze or sleep during the day. The CRC 
or nurse may wake the participant if they appear to be sleeping.  
 
On Day #6, the following will occur: 
• The participant will be allowed to smoke his/her cigarettes or electronic 
cigarette device as desired from 8am to 12am midnight.  
• The time of each cigarette or EC puff will be recorded using the TimeJot 
smartphone app or paper diary and all cigarette butts and EC devices will be 
collected at the end of the day to determine product usage. 
• The participant will wear a 24-hour ambulatory blood pressure and heart rate 
recorder for cardiovascular monitoring. 
• The participant will also be asked to fill out several Questionnaires.  
• There will also be 24-hour urine collections. 
 
On Day #7, the following will occur: 
• On the morning of Day #3, an intravenous catheter (like on Day #1) will be 
placed for blood collections every four hours from 8am to midnight, and at 
approximately 8am the next day.  
• The participant will also be asked to fill out several Questionnaires.  
• There will also be 24-hour urine collections. 
• The participant will be discharged the following morning (Study Block #2, 
Day #1) after his/her last blood draw and urine collection. 
9.4 STUDY BLOCK #2 
9.4.1 Outpatient Days 
After being discharged from the research ward, participants will be able to use 
their electronic cigarette device or tobacco cigarette product as they wish for 
another 4 outpatient days. Just as in the outpatient days for Study Block #1, they 
will use track their product use with a smartphone diary app or paper diary.  
During this outpatient period, the CRC will closely monitor participants’ entries 
in the TimeJot app or paper diary, as described in Section 9.2.3.  

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9.4.2 Admission & Inpatient Days 
The second inpatient admission will follow the same structure as the first 
inpatient admission mentioned above, but instead the participant will be 
admitted for a period of 5 days using the alternate product. 
The first 3 days of the admission will follow the same procedures as the first 
admission, with an additional two day abstinence period in which the 
participant will be asked not to use any products. During the abstinence period, 
there will be 24-hour urine collections, 24-hour cardiovascular monitoring, and 
Questionnaires.  
On Day #8, the following will occur: 
• The participant will abstain from all product use.  
• The participant will fill out several Questionnaires.  
• 8-hour urine collection from 8am-4pm followed by a 24-hour urine collection 
beginning at 4pm. 
• 24-hour ambulatory blood pressure and heart rate will begin at 8am. 
 
On Day #9, the following will occur: 
• The participant will continue with 24-hour ambulatory blood pressure 
and heart rate recorder for cardiovascular monitoring until 4pm.  
• The participant will also be asked to fill out several Questionnaires.  
• There will continue to be 24-hour urine collections until 4pm. 
9.5 Summary of Standardized Puffing Protocols  
• Electronic Cigarette ARM 1st Generation Device:  
1 puff every 30 seconds for a total of 15 puffs 
  
• Electronic Cigarette ARM 2nd/3rd Generation Devices:  
 
 
1 puff every 30 seconds for a total of 10 puffs  
 
• Tobacco Cigarette ARM:  
1 puff every 30 seconds until the cigarette is completely smoked  
 
9.6 Product Weighing Procedures 
For the EC 1st Generation Devices, our weighing procedure was the following:  

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• Pre-Outpatient Period – The CRC would label each 1st generation device 
with a sequence number using a sharpie. CRC would weigh each device 
without any product packaging.  
• Pre-standardized session – The device and/or cartridges were weighed by 
the CRC prior to the standardized session and recorded on the EC Product 
Weights Form to account for the outpatient product usage.  After this, GSH 
weighed the entire device (including the cartridge) prior to the 
standardized session and recorded this weight on the PK Product Weights 
Form.  This information was copied to the EC Product Weights form by the 
CRC, and can be found under the “Standardized Session” portion of the 
form.  
• Post-standardized session – GSH weighed the entire device (including 
cartridge) after to the standardized session and recorded this weight on the 
PK Product Weights Form.  This information was copied to the EC Product 
Weights form by the CRC, and can be found under the “Standardized 
Session” portion of the form. 
• Pre-distribution each inpatient study day – After the standardized session, 
the device and/or cartridge used in the standardized session was weighed 
again to use as a baseline for ad-lib use later in the day that did not 
included use during the standardized session.  While GSH always weighed 
the entire device for the standardized session, all other weights recorded 
during the inpatient and outpatient period were done as following: for 
disposable devices, the entire device was weighed, and for devices with 
cartridges, only the cartridge was weighed. This weight was recorded on 
the EC Product Weights Form. 
• Post-use each inpatient study day – Each study day, the nurses went into 
the participant’s room at midnight to collect their products.  The following 
morning, the CRC weighed the device and/or cartridge on the scale in the 
clean utility room, and recorded this weight on the EC Product Weights 
Form.   
For the EC 2nd or 3rd Generation  

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• Pre-Outpatient Period – The CRC would label each e-liquid vial with a 
sequence number using a sharpie. CRC would weigh each e-liquid vial 
(without the cap).  
• Pre-standardized session – The e-liquid vials that the participant used 
during the outpatient period were weighed (cap removed) by the CRC 
prior to the standardized session, and recorded on the EC Product Weights 
Form to account for the outpatient product usage.  For e-liquid vials that 
utilized a dropper, the residual e-liquid contained in the dropper was 
squeezed into the vial prior to weighing.  After this, GSH used some of the 
e-liquid to fill the device.  Then, he weighed the entire device prior to the 
standardized session and recorded this weight on the PK Product Weights 
Form.  This information was copied to the EC Product Weights form by the 
CRC, and can be found under the “Standardized Session” portion of the 
form 
• Post-standardized session – GSH weighed the entire device after to the 
standardized session and recorded this weight on the PK Product Weights 
Form.  This information was copied to the EC Product Weights form by the 
CRC, and can be found under the “Standardized Session” portion of the 
form. 
• Pre-distribution each inpatient study day – On PK days, the e-liquid vial 
used in the standardized session was weighed again to use as a baseline for 
ad-lib use later in the day that did not included use during the 
standardized session.  While GSH always weighed the entire device for the 
standardized session, all other weights recorded during the inpatient and 
outpatient period were for the e-liquid vial only.  For e-liquid vials that 
utilize a dropper, the residual e-liquid contained in the dropper was 
squeezed into the vial prior to weighing.  This weight was recorded on the 
EC Product Weights Form. 
• Post-use each inpatient study day – Each study day, the nurses went into 
the participant’s room at midnight to collect their products.  The following 
morning, the CRC weighed the e-liquid vial on the scale in the clean utility 
room, and recorded this weight on the EC Product Weights Form to 
account for the participant’s product usage the previous day.  For e-liquid 

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vials that utilize a dropper, the residual e-liquid contained in the dropper 
was squeezed into the vial prior to weighing. 
For the tobacco cigarettes, our weighing procedure was the following:  
• Pre-Outpatient Period – The CRC would weigh 1 sample tobacco cigarette 
from a pack and record as pre weight on the “Average cigarette weight” on 
the TC Products outpatient period.  
• Post-Outpatient Period – The participant collected cigarette butts and the 
CRC counted all butts and all remaining packs/cigarettes that were brought 
back. The CRC calculated the amount of tobacco burned  as: ”=(average 
cigarette weight * number of cigarettes smoked)-(average weight * number 
of cigarettes smoked). If there was a discrepancy from what the participant 
smoked and amount of cigarette they returned, the CRC evaluated the 
number of cigarette smoked and used that in the calculation above.   
• Note: the “Average cigarette weight” recorded on the TC Product Weights 
form for the outpatient period may differ in weight slightly from the 
“Average cigarette weight” on the TC Product Weights form during the 
inpatient period.  This is because when a cigarette is weighed prior to 
distribution at Orientation, it is  weighed on the scale at the Tobacco 
Research Center.  On the first day of the inpatient period (PK day), the 
cigarette is weighed on the scale in the Clean Utility Room of the hospital.  
This weight is used for the rest of the inpatient period.   
• Pre-standardized session – A cigarette from the participant’s pack was 
weighed by the CRC in the clean utility room prior to the standardized 
session, and recorded on the PK Product Weights Form and TC Product 
Weights Form.   
• Post-standardized session – After the standardized session, the CRC 
weighed the cigarette butt in the clean utility room and recorded this 
weight on the PK Product Weights Form and TC Product Weights Form. 
• Pre-distribution each inpatient study day –The weight of one cigarette 
from the participant’s pack was weighed in the clean utility room on the 
first inpatient study day, and recorded under the “Average cigarette 
weight” portion of the TC Product Weights form.  The weight of this 
cigarette was used as the average cigarette weight for all other inpatient 

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study days.  Each day, the number of cigarettes distributed was recorded 
on the TC Product Weights Form.   
• 
Post-use each inpatient study day – Each study day, the nurses went into 
the participant’s room at midnight to collect their products.  The following 
morning, the CRC weighed the returned cigarette butts in the clean utility 
room and recorded this weight on the TC Product Weights Form to 
account for the participant’s product usage the previous day. Under 
returned products, the “Total Weight” is equal to average cigarette weight 
* number of cigarette butts. “Average Weight” is equal to Total 
Weight/number of cigarette butts. “Tobacco Burned”=(average cigarette 
weight * number of cigarettes smoked)-(total weight).  In cases where the 
participant was missing a butt or returned an extra butt, the “Tobacco 
Burned” was calculated as: ”=(average cigarette weight * number of 
cigarettes smoked)-(average weight * number of cigarettes smoked).   
9.7 PARTICIPANT COMPENSATION 
Participants will be compensated according to Table 2: 
Table 2 
 
Screening 
Visit 
Study Block #1 
Study Block #2 
Completion Bonus 
Compensation 
$30* 
$600 
$900 
$500 
Total 
Compensation 
 
 
 
$2,030 
*Compensation for the screening visit will be contingent upon a negative 
toxicology drug screen (THC is okay) and a cotinine of ≥ 50 ng/mL. 
Compensation for participants who drop-out and do not make it through all 
portions of the study is described in Section 5.1.2.  
10 ADVERSE EVENTS AND PROTOCOL DEVIATIONS 
10.1 
SAFETY MONITORING 
During the inpatient stay, participants will be monitored by the CRC and the 
nursing staff who will directly contact the Study Physician in case of any 
subsequent adverse events. If the participants experience adverse effects, the 
Study Physician will evaluate this with them and decide if they should be 
withdrawn from this study. 

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10.2 
REPORTING ADVERSE EVENTS 
Reporting of serious adverse events will follow the current requirements of the 
Institutional Review Board (IRB), with the concurrent reporting to the Nurse 
Manager at the CRC. Specifically, the following will be reported within five (5) 
working days of the Principal Investigator’s (PI) awareness, in writing:  
• All serious adverse events associated with  the study procedures and/or 
• Any incidents or problems involving the conduct of the study or patient 
participation, including problems with the recruitment and/or consent 
process. The PI will provide a discussion of such events to the IRB on an 
annual basis during study renewal. 
• Any incidents or questionable adverse events are discussed at the weekly 
staff meetings with the PI.  
The standard adverse event grading scale will be used to report any potential 
adverse advents from phlebotomy, study drug, or other study procedures:  
• Grade 1 - Mild AE: did not require treatment 
• Grade 2 - Moderate AE: resolved with treatment 
• Grade 3 - Severe AE: resulted in inability to carry on normal activities and 
required profession medical attention 
• Grade 4 - Life-threatening or disabling AE 
• Grade 5 - Fatal AE 
The supervising Study Physician will be notified of all Grades 2 through 5 AEs. 
Additionally, the PI will be notified of all grades 4 and 5 AEs. Grades 3 through 5 
AEs will be reported to the CCRC and the IRB. Grades 4 and 5 will be reported 
within 24 hours. Grade 3 will be reported within 20 days. Grade 2 will be 
included in the yearly progress report. Grade 1 will not be reported. 
10.3 
PROTOCOL DEVIATIONS & VIOLATIONS 
Protocol deviations are defined as an event that deviates from the defined study 
protocol, but does not pose any risk to the participant or harm to the quality of 
the study data. For example, a follow-up call may be conducted outside of the 
stipulated window, or a section of questions on a questionnaire may be missed 
due to a mistake in branching. Deviations will be recorded on a protocol 
deviation sheet and reviewed and signed by the PI. 
 
Protocol violations are events that deviate from the defined study protocol, but 
put the participant at risk and/or cause harm to the study data. Protocol 

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violations will be recorded on a protocol violation sheet, reviewed and signed by 
the PI and reported to the IRB. 
11 DATA COLLECTION AND MANAGEMENT 
11.1 
DATA COLLECTION FORMS 
All of the following measures will be collected.  
Screening Process:  
• UCSF Tobacco Research Email Screen 5/26/2015-2/23/18  
• E-Cigarette R01 & Flavors Study Screen (04/01/2015-05/26/2015) 
In-Person Screening Visit:  
• MILCOM 
• Screening Packet 
Inpatient Study Visits: 
• Day 5, Block 1 & 2:  
o Outpatient Withdrawal Form 
o Questionnaire of Smoking Urges (QSU) or  modified for E-Cigarettes 
o Cigarette Evaluation Scale (mCES) or modified for E-Cigarettes 
o Positive and Negative Affect Scale (PANAS)  
o Minnesota Behavioral Scale (MNWS) 
• Day 6, Block 1 & 2:  
o Questionnaire of Smoking Urges (QSU) or  modified for E-Cigarettes 
o Cigarette Evaluation Scale (mCES) or modified for E-Cigarettes 
o Positive and Negative Affect Scale (PANAS)  
o Minnesota Behavioral Scale (MNWS) 
• Day 7, Block 1 & 2:  
o Questionnaire of Smoking Urges (QSU) or  modified for E-Cigarettes 
o Cigarette Evaluation Scale (mCES) or modified for E-Cigarettes 
o Positive and Negative Affect Scale (PANAS)  
o Minnesota Behavioral Scale (MNWS) 
• Day 8, Block 2:  
o Questionnaire of Smoking Urges (QSU) or  modified for E-Cigarettes 
o Positive and Negative Affect Scale (PANAS)  
o Minnesota Behavioral Scale (MNWS) 
• Day 9, Block 2: 

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o Questionnaire of Smoking Urges (QSU) or  modified for E-Cigarettes 
o Positive and Negative Affect Scale (PANAS)  
o Minnesota Behavioral Scale (MNWS) 
o End of Study Questionnaire 
Information on how data is stored, processed and analyzed can be found in the 
Data Safety and Monitoring Plan.  
12 DUTIES AND RESPONSIBILITIES OF STAFF 
12.1 
PRINCIPAL INVESTIGATOR 
The Principal Investigator is responsible for study design and oversight of 
implementation, data analysis, and manuscript preparation. 
12.2 
CO-PRINCIPAL INVESTIGATORS 
The Co-Principal Investigators are responsible for study design and oversight of 
implementation, data analysis, and manuscript preparation, with the assistance 
of the Principal Investigator. 
12.3 
STUDY PHYSICIAN 
The Study Physician is responsible for medical study chart review and eligibility 
determination, medical history and physical examination at SFGH admissions, 
and other medically related expertise. 
12.4 
PROJECT MANAGER 
The Project Manager is responsible for overall functioning of study coordination 
with IRB protocols; monitoring of study budget and coordination with 
departmental administrative personnel; supervision of research associates; 
management of clinic facilities.  
12.5 
CLINICAL RESEARCH COORDINATOR 
The CRC will oversee study logistics including consenting and screening 
participants, conducting study visit procedures, coordinating inpatient 
admissions and procedures with nursing staff at the research ward, coordinating 
specimen testing with laboratory, overseeing participant reimbursement, 
maintaining study charts and data entry. 
 
 

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APPENDIX A: DATABASE GUIDE 
 
Schedule of Assessments 
The Schedule of Assessments is a list detailing the various specimens, forms, and 
questionnaires that are taken and administered throughout the study on any given 
study visit/study day.  Additionally, this form lists the number of samples taken, the 
analysis type for each specimen, the sample labels before and after processing, and the 
number of aliquots post-sample processing.  
• Location: t-Drive 
• Folder: 6885 Crossover E-Cigarettes 
• Sub-folder 1: Databases 
• Subfolder 2: Schedule of Assessments 
• name “Updated Schedule of Assessments 3.9.18”  
Screening Visit  
1. Screening Log 

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The Screening Log is a list of all participants who came into the 20th street 
Tobacco Research Center for a screening visit for the Crossover study.  This log 
details information about each participant as well as the outcome of the visit.  
Specifically, the Screening Log contains the following information: participant’s 
name, date of screening visit, RedCap ID from the RedCap pre-screening email 
survey, study ID number, toxicology and pregnancy screening results, eligibility 
status and reason, ethnicity, race, sex, 5B status (including whether or not the 
participant was a no-show)and 5B start and end date. 
• Location: t-Drive 
• Folder: 6885 Crossover E-Cigarettes 
• Sub-folder 1: Databases 
• Subfolder 2: Screening 
• name “#6685 Participant Log & Tallies”  
• Password: 6885enr 
2. Saliva Cotinine Screening Log 
The Saliva Screening Log is a list of the cotinine values for participants who came 
in for a Crossover screening visit.   
• Location: s-Drive 
• Folder: Clinical Research 
• Sub-folder 1: Screening Log  
• Subfolder 2: E-Cigarette Crossover Study 
• name “ECigarette Crossover Saliva Cotinine Screening Log”  
3. Eligible Participant’s Log (only participants deemed eligible at screening) 
The Eligible Participant’s Log is a list of all participants deemed eligible to 
participate in the Crossover study after their screening visit.  This log contains 
the following information: participant’s name, study ID, product assignment 
number, starting product, MRN number, 5B admission and discharge date, and 
notes regarding withdrawals, no-shows and early discharges.   Overall, we had 
54 eligible participants, and 36 completed participants. 
• Location: t-Drive 
• Folder: 6885 Crossover E-Cigarettes 
• Sub-folder: Databases 
• name “#6685 Eligible Participants Log”  
 

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4. E-Cigarette Crossover Database 
The data collected at the screening visit is located on RedCap under the project 
titled E-Cigarette Crossover Database.  This project includes the following forms: 
Participant Summary Form, Screening Eligibility Checklist, Screening Packet, 
Physiological Assessment, NDSS, CES-D, and Wisconsin Inventory of Smoking 
Dependence Motives. 
• Location: https://redcap.ucsf.edu/redcap_v8.1.7/index.php?pid=10780 
5. Product Photo Database 
The product photos for each participant who came in for a screening visit are 
located on the Product Photos Database.  
a. Location: t-Drive 
b. Folder: 6885 Crossover E-Cigarettes 
c. Sub-folder: Study Coordinator Files 
d. folder name “Product Photos”  
Full Study Participant Data 
1. Inpatient Caffeine Log 
The Inpatient Caffeine Log details caffeine intake for participants during their 
inpatient study days. 
a. Location: t-Drive 
b. Folder: 6885 Crossover E-Cigarettes 
c. Sub-folder: Databases 
d. name “#6685 Participant Caffeine Intake”  
2. E-Cigarette Device Summary 
The E-Cigarette Device Summary is a list of the device names, generation and e-
liquid constituents that each participant used during the study.  
a. Location: t-Drive 
b. Folder: 6885 Crossover E-Cigarettes 
c. Sub-folder: Databases 
d. name “#6885 Crossover E-Cigarette Devices Summary” 
3. Crossover Specimen Log 
The Crossover Specimen Log is a file is a database used to track all of the 
specimens collected during participants’ orientation visit and inpatient study 
days.  This log contains the following information: specimen type, dates and 

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times of specimen collection, date of lab sample transfers, and volume/pH of 
urine specimens. 
a. Location: t-Drive 
b. Folder: Clinical Research Operations 
c. Sub-folder 1: Lab Processing and Reference 
d. Sub-folder 2: Specimen Logs 
e. name “6885 6885 E-Cig XO Specimen Log” 
4. Urine Catecholamine Summary 
The Urine Catecholamine Summary contains the catecholamine data from each 
participant, including: creatinine, epinephrine, and dopamine per volume, per 24 
hours, and ratio to CRT. 
• Location: t-Drive 
• Folder: 6885 Crossover E-Cigarettes 
• Sub-folder 1: Databases 
• Sub-folder 2: Urine Catecholamines 
• name“#6885 Urine Catecholamine Summary” 
• Information is downloaded from ARUP Labs using the login information 
below, then saved in the Urine Catecholamine Summary excel file 
i. Website: https://www.aruplab.com/ii/login.jsp  
ii. Username: ucsftobacco 
iii. Password: Tobacco1! 
5. Product diaries (for participants who used TimeJot app) (source data)  
The product diaries database is where the diaries are saved for participants that 
used the Time Jot app.  All other diary entries can be found as the paper version 
in the participant’s binder, or on RedCap. 
a. Location: t-Drive 
b. Folder: 6885 Crossover E-Cigarettes 
c. Sub-folder 1: Databases 
d. Sub-folder 2: Product Diaries 
6. Cardiovascular Monitoring (source data)  
The Cardiovascular Monitoring database is where the CV data can be found for 
all participants.   
a. Location: t-Drive 
b. Folder: 6885 Crossover E-Cigarettes 

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c. Sub-folder 1: Databases 
d. Sub-folder 2: 24 hour Cardiovascular Monitoring 
7. E-Cigarette Crossover Database  
The E-Cigarette Crossover Database is a database in RedCap where most study 
data has been entered.  This database includes the following forms: Product 
Accountability Form, Product Weight Form, product diaries, inpatient 
participant weights, Pre-Standardized Questionnaire, Post-Standardized 
Questionnaire, 2-Hour Abstinence Questionnaire, 4-Hour Abstinence 
Questionnaire, 8am Ad-Lib Questionnaire, 8:15 am Ad-Lib Questionnaire, 12pm 
Ad-Lib Questionnaire, 4pm Ad-Lib Questionnaire, 8pm Ad-Lib Questionnaire, 
8am Abstinence Questionnaire, 12pm Abstinence Questionnaire, 4pm Abstinence 
Questionnaire, 8pm Abstinence Questionnaire, 24-hour cardiovascular 
monitoring data, 48-hour Product Use Form, End of Study Questionnaire, 
Withdrawal Symptoms Questionnaire, and adverse event reports.  
• Location: https://redcap.ucsf.edu/redcap_v8.1.7/index.php?pid=10780 
 
8. 6885 CV Data (cleaned data)  
The 6885 CV Data is a project in RedCap that includes the CV data from all 
Crossover participants.  Individual data points on this project may differ slightly 
from those on the 24-hour cardiovascular monitoring form on the E-Cigarette 
Crossover Database.   The cardiovascular data on the E-Cigarette Crossover 
Database was entered into RedCap manually, whereas the data on this project 
was imported directly into RedCap from the source. 
 
9. 6885 Diary Data (cleaned data)  
The 6885 Diary Data is a project in RedCap that includes the diary data from 
Crossover participants.  Individual data points on this project may differ slightly 
from those on the product diary form on the E-Cigarette Crossover Database.   
The product diary data on the E-Cigarette Crossover Database was entered into 
RedCap manually, whereas some of the data on this project was imported 
directly into RedCap from the source. 
 
 
 

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APPENDIX B: STUDY POST-MORTEM 
• Eating times on nurses flow sheets. Indicate exactly when it is okay for them to 
eat, around study procedures.  
• Get 6mL of e-liquid for Gideon ahead of time, prior to the PK day for e-cig 
• The study procedures need to be changed so that participants do not get the $30 
bonus check if they vaped the morning of PK day, rather than just having the 
CO<5 requirement.  
o $30 gift card that morning if they abstain 
o We will do Expired CO 
o We will do “bogus pipeline” for vaping  
o We will tell them that we are checking for both  
• MD orders and nurses flowsheets should specify that single stick blood draws 
using a butterfly needle are okay at the participant’s request.  Some participant’s 
preferred this and Delia had to write this in the orders each time.  
• Specify the pre-blood draw on the nurses flowsheets as its own discrete step on 
PK days. 
• Have the nurses check on the participant’s ABPM every 4 hours or so (put in 
nurses flowsheets).  Instruct the nurses to press the manual button if there are 
repeated errors.  
• Get rid of the note page on each inpatient questionnaire.  
o CRC notes should just be recorded on the session log.  
• Get rid of the volume portion on the EC product weights form (unless we start 
using mathematical formula using starting volume, initial wt. and final wt. to 
calculate exact volume used).  
• In the nurses flowsheet on the mornings when the ABPM will be placed, write in 
something along the lines of “Do NOT let the participant shower after 7:30 AM).   
• Have the nurses place the cuff instead of the CRC, but CRC can do the first 
reading or we train them to turn on and do it.