A Randomized, Controlled, Parallel Group Clinical Study of Cigarette Smokers Using an Innovative Oral Tobacco-derived Nicotine Product to Determine Impact on Cigarette Consumption and Biomarkers of Exposure
Phase: NA
Conditions: Tobacco Use
Sponsor: Altria Client Services LLC

A Randomized, Controlled, Parallel Group Pilot Clinical Study to Determine Changes in 
Biomarkers of Exposure (BOE) in Adult Smokers Allowed ad libitum VBM-FG2 Disc Use 
Relative to Adult Smokers Not Allowed VBM-FG2 Disc Use 
NCT04079933 
20AUG2013 
 

 
Protocol No: COV-VER-01-13 
 
Issue Date Amendment 1: 20 August 2013 
 
 
 
 
 
 
 
Protocol Number: COV-VER-01-13 
 
Protocol Name: A Randomized, Controlled, Parallel Group Pilot Clinical Study to 
Determine Changes in Biomarkers of Exposure (BOE) in Adult Smokers Allowed 
ad libitum VBM-FG2 Disc Use Relative to Adult Smokers Not Allowed VBM-FG2 
Disc Use 
 
 
PILOT AMBULATORY VBM-FG2 EXPOSURE (PAVE) STUDY 
 
 
 
Final Protocol Issue Date: 09 August 2013  
Amendment 1 Issue Date: 20 August 2013 
 
Sponsor: 
Altria Client Services, Inc. (ALCS) 
P.O. Box 26583 
Richmond, VA  23261-6583 
 
 
 
 
 
 
 
 
Sponsor Contact: 
 
 
 
 
 
 
HIGHLY CONFIDENTIAL – PROPRIETARY INFORMATION 
Page 1 of 68 
 

 
Protocol No: COV-VER-01-13 
 
Issue Date Amendment 1: 20 August 2013 
 
 
Investigators 
 
and Study Sites: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The information contained herein is Highly Confidential and the proprietary 
property of Altria Client Services and any unauthorized use or disclosure of such 
information without prior written authorization of Altria Client Services is 
expressly prohibited. 
HIGHLY CONFIDENTIAL – PROPRIETARY INFORMATION 
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Protocol No: COV-VER-01-13 
 
Issue Date Amendment 1: 20 August 2013 
 
TABLE OF CONTENTS 
 
SYNOPSIS ..................................................................................................................................................... 9 
1 
INTRODUCTION ............................................................................................................................. 12 
1.1 
BACKGROUND ................................................................................................................................. 12 
1.2 
RATIONALE ...................................................................................................................................... 13 
2 
PURPOSE AND STUDY OBJECTIVES ........................................................................................ 14 
2.1 
PURPOSE .......................................................................................................................................... 14 
2.2 
PRIMARY OBJECTIVE ....................................................................................................................... 14 
2.3 
SECONDARY OBJECTIVES ................................................................................................................ 14 
3 
STUDY DESIGN AND EVALUATION .......................................................................................... 15 
3.1 
STUDY DESIGN ................................................................................................................................ 15 
3.2 
STUDY POPULATION ........................................................................................................................ 17 
4 
SUBJECT SELECTION AND DISCONTINUATION .................................................................. 18 
4.1 
INCLUSION ....................................................................................................................................... 18 
4.2 
EXCLUSION ...................................................................................................................................... 19 
4.3 
SUBJECT DISCONTINUATION ............................................................................................................ 20 
5 
STUDY CONDUCT ........................................................................................................................... 21 
5.1 
ETHICS ............................................................................................................................................. 21 
5.2 
RANDOMIZATION AND ADMINISTRATION ........................................................................................ 21 
5.3 
BLINDING/UNBLINDING ................................................................................................................... 21 
5.4 
PROHIBITED MEDICATIONS DURING THE STUDY ............................................................................. 22 
6 
STUDY PROCEDURES AND OBSERVATIONS ......................................................................... 23 
6.1 
TIME AND EVENTS SCHEDULE ......................................................................................................... 23 
6.2 
PROCEDURES BY VISIT ..................................................................................................................... 25 
6.3 
DETAILS OF PROCEDURES ................................................................................................................ 27 
7 
CLINICAL SUPPLIES ..................................................................................................................... 32 
7.1 
TEST PRODUCT ................................................................................................................................ 32 
7.2 
PACKAGING AND LABELING ............................................................................................................ 33 
7.3 
STORAGE, HANDLING AND DISPENSING ........................................................................................... 33 
7.4 
TEST PRODUCT RECORDS AT STUDY SITES ...................................................................................... 34 
7.5 
RETURN AND DESTRUCTION OF TEST PRODUCT .............................................................................. 34 
8 
ADVERSE EVENT REPORTING IN CLINICAL TRIALS ........................................................ 35 
8.1 
ADVERSE EVENTS ............................................................................................................................ 35 
8.2 
SERIOUS ADVERSE EVENTS ............................................................................................................. 37 
8.3 
ADVERSE EVENT/SERIOUS ADVERSE EVENT FOLLOW-UP ............................................................... 38 
8.4 
PREGNANCY..................................................................................................................................... 38 
9 
DATA MANAGEMENT ................................................................................................................... 38 
9.1 
DATABASE DESIGN AND CREATION ................................................................................................. 38 
9.2 
DATA CODING ................................................................................................................................. 38 
9.3 
DATA ENTRY AND VERIFICATION .................................................................................................... 39 
9.4 
STUDY RESULTS DATA TRANSFER ................................................................................................... 39 
9.5 
DATA VALIDATION .......................................................................................................................... 39 
9.6 
DATABASE LOCK ............................................................................................................................. 39 
10 
STATISTICS ...................................................................................................................................... 39 
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Protocol No: COV-VER-01-13 
 
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10.1 SAMPLE SIZE DETERMINATION ........................................................................................................ 39 
10.2 CRITERIA FOR EVALUATION ............................................................................................................ 39 
10.3 DATA SET DESCRIPTIONS ................................................................................................................ 40 
10.4 DATA SET ANALYSES ...................................................................................................................... 40 
10.5 ACCOUNTING FOR MISSING, UNUSED, AND SPURIOUS DATA ........................................................... 42 
11 
QUALITY ASSURANCE ................................................................................................................. 42 
11.1 COMPLIANCE WITH PROTOCOL AND PROTOCOL REVISIONS ............................................................. 42 
11.2 MONITORING FOR PROTOCOL COMPLIANCE .................................................................................... 43 
12 
ETHICAL AND LEGAL CONSIDERATIONS ............................................................................. 43 
12.1 INSTITUTIONAL REVIEW BOARD ...................................................................................................... 43 
12.2 INFORMED CONSENT ........................................................................................................................ 43 
12.3 CONFIDENTIALITY ........................................................................................................................... 44 
13 
ADMINISTRATIVE ......................................................................................................................... 45 
13.1 RECORDS AND REPORTS .................................................................................................................. 45 
13.2 RECORDS RETENTION ...................................................................................................................... 45 
13.3 SPONSOR .......................................................................................................................................... 46 
13.4 INVESTIGATORS, STUDY SITES, AND INSTITUTIONAL REVIEW BOARDS ........................................... 46 
13.5 CENTRAL ORGANIZATIONS AND/OR VENDORS ................................................................................ 46 
14 
GLOSSARY OF TERMS AND LIST OF ABBREVIATIONS ..................................................... 47 
14.1 LIST OF ABBREVIATIONS ................................................................................................................. 47 
15 
REFERENCES .................................................................................................................................. 49 
APPENDICES 
APPENDIX 1  INVESTIGATOR OBLIGATIONS ................................................................................. 50 
APPENDIX 2: SUBJECT SCREENER / TOBACCO HISTORY .......................................................... 54 
APPENDIX 3: POTENTIAL PURCHASE INTEREST QUESTIONNAIRE ....................................... 57 
APPENDIX 4: FAGERSTRÖM TEST FOR CIGARETTE DEPENDENCE1...................................... 58 
APPENDIX 5: PAST 7 DAY CIGARETTES USE QUESTIONNAIRE ................................................ 59 
APPENDIX 6: OTHER TOBACCO OR NICOTINE CONTAINING PRODUCT USE 
QUESTIONNAIRE ........................................................................................................................... 60 
APPENDIX 7: QUIT ATTEMPTS AND QUITTING INTENTIONS QUESTIONNAIRE – DAY 1 . 63 
APPENDIX 8: QUIT ATTEMPTS AND QUITTING INTENTIONS QUESTIONNAIRE - END OF 
STUDY ................................................................................................................................................ 64 
APPENDIX 9: PROTOCOL AMENDMENTS ........................................................................................ 65 
FIGURES 
FIGURE A:  STUDY DESIGN .................................................................................................................. 16 
TABLE A:  SAMPLES FOR ANALYSIS OF URINARY BIOMARKERS OF EXPOSURE ............. 31 
TABLE B:  BLOOD SAMPLE VOLUMES ............................................................................................. 31 
 
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Protocol No: COV-VER-01-13 
 
Issue Date Amendment 1: 20 August 2013 
 
 
SYNOPSIS 
 
ALCS Protocol Number:   
COV-VER-01-13 
Abbreviated Protocol Title:   
PILOT AMBULATORY VBM-FG2 EXPOSURE (PAVE) STUDY 
Long Protocol Title:   
A Randomized, Controlled, Parallel Group Pilot Clinical Study to Determine Changes in Biomarkers of 
Exposure (BOE) in Adult Smokers Allowed ad libitum VBM-FG2 Disc Use Relative to Adult Smokers not 
Allowed VBM-FG2 Disc Use. 
Study Sites:  3 
Study Objectives: 
The primary objective of this study is to: 
• 
Compare the differences in percent change in urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-
butanol (NNAL) from Baseline to End of Study between adult smokers randomly assigned to Test 
Group (ad libitum VBM-FG2 use) and Control Group (no VBM-FG2).  
 
The secondary objectives of this study are to: 
• 
Compare the difference in biomarkers of exposure (BOE; urinary total NNAL, 
nicotine metabolites, S-phenylmercapturic acid [S-PMA], blood carboxyhemoglobin [COHb] and 
exhaled carbon monoxide [CO]) and cigarettes per day (CPD) between two methods for 
determining CPD during the Baseline Period: 
o 
Recall of average daily CPD for prior week using Past 7 Day Cigarettes Use 
Questionnaire (Day 1). 
o 
Daily CPD tracking using an interactive voice response system (IVRS; 7 day average of 
values recorded on Days 2 through 8).  
• 
Compare the differences in percent change in urinary nicotine equivalent [NE], S-PMA, blood 
COHb, exhaled CO, and CPD from Baseline to End of Study between adult smokers randomly 
assigned to Test Group (ad libitum VBM-FG2 use) and Control Group (no VBM-FG2).  
• 
Compare the changes in all BOE and CPD from Baseline to End of Study between Test Group and 
Control Group over 4 weeks. 
• 
Characterize subgroups based on change in CPD from Baseline to End of Study (no change, <50% 
reduction, ≥50% reduction, 100% reduction, increase) within each study group. 
• 
Characterize subgroups based on change in total NNAL from Baseline to the End of Study (no 
change, reduction, increase) in each study group. 
• 
Compare changes in the Fagerström Test for Cigarette Dependence from Baseline (Day 8) to End 
of Study within and between each study group. 
• 
Compare changes on the Quit Attempts and Quitting Intentions from Baseline (Day 1) to End of 
Study within and between each study group. 
 
 
The Baseline Period is from Day 1 to Day 8.  Statistically, “Baseline” will be defined as a single time point 
at the end of the Baseline Period (except where noted).  The last study visit will be defined as End of Study. 
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Protocol No: COV-VER-01-13 
 
Issue Date Amendment 1: 20 August 2013 
 
 
Study Design/Visit Schedule:   
This is a randomized, controlled, open-label, parallel group, multi-center, 5-week pilot study to determine 
changes in BOE in adult smokers allowed ad libitum use of VBM-FG2 (Test Group) relative to adult 
smokers who are not allowed used of VBM-FG2 (Control Group).  This study will be conducted in 
approximately 150 adult smokers randomized in a 3:2 ratio (Test: Control) with no more than a 60:40 
distribution of either males or females to either group. 
 
Screening (Day -28 to Day -1): 
1. Visit 1/Screening (Day -28 to Day -1) 
2. VBM-FG2 product trial 
 
Baseline Period (Day 1 to Day 8): 
3. Visit 2 (Day 1) 
4. Visit 3 (Day 8 ± 1 day) - randomization 
Electronic IVRS conducted daily (Days 1 to 8) 
 
Product Use Period (Day 8 – Day 36): 
5. Visit 4 (Day 15 ± 1 day) 
6. Visit 5 (Day 22 ± 1 day) 
7. Visit 6 (Day 29 ± 1 day) 
8. Visit 7/End of Study (Day 36 ± 1 day) 
Electronic IVRS conducted daily (Days 8 to 36) 
Number of Subjects per Group:   
Approximately 150 subjects will be randomized (based on gender, daily cigarette consumption [≤20 and 
>20], and quit attempts [any quit attempt/ no quit attempts]) in a 3:2 ratio (not more than 60:40 distribution 
of either male or female) to the Test:Control Group.  
Group 1 (Test) 
• 
Adult smokers provided VBM-FG2 discs for ad libitum use (n = 90) 
Group 2 (Control) 
• 
Adult smokers not provided VBM-FG2 discs (n = 60) 
Subject Population:   
The study population will consist of approximately 150 adult (21 to 65 years of age, inclusive) cigarette 
smokers across 3 study sites.  
Study Duration:  
The expected duration of the study, from first subject, first visit through last subject, last visit will be 
approximately 3 months.  The expected study duration for each individual subject is approximately 
5 weeks (potentially 9 weeks from Screening to end of Study). 
Statistics:   
The purpose of this Pilot Study is to collect data to estimate the variability of the primary outcome, which 
will be used to estimate the sample size for a future pivotal study.  The sample size for this study is 
believed to be appropriate based on statistical principles for pilot studies. 
 
Primary Outcome Measures 
• 
Differences in the percent change from Baseline to End of Study in urinary total NNAL   between 
the Test and Control Groups 
 
Secondary Outcome Measures 
• 
Differences in all BOE during the Baseline Period between Day 1 (weekly recall) versus Day 8 
(daily tracking using IVRS).  
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Protocol No: COV-VER-01-13 
 
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• 
Differences in CPD during the Baseline Period between once weekly recall (Days 1 and 8) versus 
daily tracking (average of recordings on Days 2 through 8). 
• 
Differences in the percent change from Baseline to End of Study in the other BOE (urinary NE, 
S-PMA, blood COHb, exhaled CO) and CPD between the Test and Control Groups. 
• 
Differences from Baseline to End of Study in all BOE and CPD between the Test and Control 
Groups. 
• 
Proportion of subjects in subgroups based on cigarette consumption change from Baseline to End 
of Study (no change, <50% reduction, ≥50% reduction, 100% reduction, increase) within and 
between  the Test and Control Groups. 
• 
Proportion of subjects in subgroups based on total NNAL change from Baseline to End of Study 
(no change, reduction, increase) within each group. 
• 
Changes from Baseline (Day 8) to End of Study in Fagerström Test for Cigarette Dependence, 
within and between the Test and Control Groups. 
• 
Changes from Baseline (Day 1) to End of Study on the Quit Attempts and Quitting Intentions, 
within and between the Test and Control Groups. 
 
Statistically, “Baseline” will be defined as a single time point at the end of the Baseline Period unless 
otherwise noted.  The last study visit will be defined as End of Study.  
 
Statistical methods 
 
Descriptive statistics 
Descriptive statistics will be used to characterize the data during the Baseline Period and over time.  All 
summaries of categorical data will present frequency counts and proportions.  All summaries of continuous 
data will present the number of non-missing values, mean, median, standard deviation, minimum, 
maximum, coefficient of variation, and 95% confidence interval.   
 
Primary outcome measure analyses 
A linear mixed model for repeated measures analysis of variance will be used for the analyses of the 
primary outcome measure.  The terms of the model will be outlined in the statistical analysis plan.  SAS 
procedure Proc Mixed will be used for the statistical computing. 
 
Secondary outcome measure analyses 
A linear mixed model for repeated measures analysis of variance will be used for the analyses of the 
secondary outcome measures.  The model will include terms for study group (or tracking method for 
cigarette consumption), study visit and subject.  SAS procedure Proc Mixed will be used for the statistical 
computing. 
 
For correlations, a linear regression analysis will be conducted to examine the relationships between levels 
of biomarkers (dependent variable) with either the weekly cigarette counts (independent variable) or the 
daily cigarette counts.  The coefficients of determination will be compared. 
 
The Mantel-Haenszel Chi-Square Test will be used to test the frequency differences of product use 
categories between the 2 groups. 
 
Interim Analysis:  
An interim data analysis will be conducted after the first 50 (approximately 30 Test Group and 20 Control 
Group) subjects have completed the study.  The purpose of the analysis is to obtain timely information for 
the planning of a proposed pivotal study. 
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Protocol No: COV-VER-01-13 
 
Issue Date Amendment 1: 20 August 2013 
 
1 INTRODUCTION 
1.1 Background  
The harm caused by tobacco use is primarily attributable to cigarette smoking.  Despite 
the known health consequences, millions of adults are likely to continue smoking.  
Discouraging initiation and promoting cessation are and should remain core strategies to 
reduce tobacco-related harm; however, it is unlikely that they will eliminate tobacco use 
altogether.  Transitioning adult smokers from cigarettes to demonstrably less hazardous 
non-combustible tobacco products could positively impact smoking cessation (number of 
years smoked) and number of cigarettes per day (CPD).   
Altria Client Services (ALCS) is committed to the development of less harmful tobacco 
product alternatives for adult cigarette smokers.  There is overwhelming scientific 
evidence regarding a risk continuum in the range of tobacco products currently available 
on the market.  According to this body of evidence, cigarettes are the most risky tobacco 
product and smokeless tobacco products present relatively lower risks1.  Making 
available lower risk tobacco products for those adult smokers that do not quit smoking, 
can complement strategies that have been proven to reduce harm from cigarette smoking 
(i.e., smoking cessation and discouraging initiation). 
1.1.1 Product information 
Altria Client Services has developed a new tobacco product; VBM-FG2.  VBM-FG2 
discs are oral, non-dissolvable products containing tobacco-derived nicotine that may 
provide an opportunity for adult cigarette smokers to move down the continuum of risk.  
VBM-FG2 discs are a tobacco-derived nicotine product designed to appeal to adult 
cigarette smokers who are interested in tobacco product alternatives to cigarettes. 
VBM-FG2 discs are designed to be spit-free and chewable.  
The product consists of a polymer matrix, which is embedded with a cellulose fiber that 
meets or exceeds the monograph requirements for Powered Cellulose as published in the 
Food Chemicals Codex, 4th Edition.  The matrix also contains flavors that are generally 
recognized as safe. 
The polymer being used meets the requirements of the FDA-modified ISO 10933, Part 1 
“Biological Evaluation of Medical Devices” tests for materials in contact with human 
tissue with a contact time of 30 days or less.  The nicotine is pharmaceutical grade, 
derived from tobacco obtained from a facility that operates under FDA’s Good 
Manufacturing Practice regulations for pharmaceutical active ingredients.  The level of 
nicotine in a VBM-FG2 disc is approximately 1.5 mg.  The amount of nicotine in a 
VBM-FG2 disc is lower than the range of nicotine typically found in pouched smokeless 
tobacco products currently on the market.  
1.1.2 Previous human studies 
A previous version of VBM-FG2 (VBM-FEXP) has been sold in a lead market in the Commonwealth of 
Virginia since June, 2012.  This product is very similar to the product being tested, it contains 1.5 mg 
tobacco-derived nicotine and has similar ingredients except that the VBM-FG2 has a softer texture.  Before 
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Protocol No: COV-VER-01-13 
 
Issue Date Amendment 1: 20 August 2013 
 
introduction of VBM-FEXP to the market a pharmacokinetic (PK) study was conducted with 2 prototype 
products (11-SOLID-OOE-45 and 11-SOLID-OOE-46 containing 1 and 2 mg tobacco derived nicotine, 
respectively) in December 2011.  The purpose of this study was to characterize the nicotine plasma PK 
profile from a single use of the prototypes.  This randomized, single-blind, 2-period crossover PK study 
(study number: CEL-SOL-01-11) was conducted in 18 (M/F = 9/9) healthy adult smokers following single 
use of the 2 prototypes.  Subjects were allowed to use 1 of the 2 prototype oral tobacco products by 
chewing them and moving them around in the mouth, as desired, for 30 minutes on Day 1 and crossed over 
to the other test product on Day 2 of the study.  Blood samples for plasma nicotine concentration were 
drawn on Days 1 and 2 at 5 minutes prior to and 2, 4, 8, 12, 16, 20, 30, 45, 60, 90, 120, 240, 480, and 
720 minutes following placement of the test product in the mouth. 
The geometric mean baseline-adjusted maximum observed concentration values for nicotine were 1.40 and 
2.51 ng/mL for 11-SOLID-OOE-45 and 11-SOLID-OOE-46, respectively, and the geometric mean area 
under the concentration-time curve from Hour 0 to the last measurable concentration values for nicotine 
were 5.69 and 9.73 ng·hr/mL for 11-SOLID-OOE-45 and 11-SOLID-OOE-46, respectively.  Maximum 
nicotine plasma concentrations were reached by approximately 0.65 hours while mean half-life was 
between 3 and 4 hours, regardless of the dose administered or gender. 
Six (33%) subjects experienced a total of 11 mild adverse events (AEs) over the course of 
the study.  The most common AE was throat irritation (4 subjects), followed by dyspepsia 
(2 subjects) and nausea (2 subject).  Based on the results of this study it was determined 
that single administrations of the VBB-FG2 disc prototypes yielded rate and extent of 
nicotine absorption that were linear and approximately dose proportional for the 2 mg 
prototype compared to the 1 mg prototype.  Single administrations of non-dissolvable 
VBM-FEXP prototypes containing 1 and 2 mg tobacco-derived nicotine was well 
tolerated in this group of healthy male and female adult smokers.   
In addition to this study, ALCS has conducted several consumer research studies of 
varying durations of exposure.  Of particular note was an extended home use test over a 
period of 12-weeks among adult smokers, ages 21 to 54 years, to understand tobacco 
product use behavior.  The products were well tolerated by the participants in this 
12-week study (n = 284).   
Furthermore, ALCS continuously monitors consumer calls to the Consumer Response 
Center (CRC).  As of June 27, 2013, since the launch of the previous version of 
VBM-FG2, the CRC has received 2 calls considered to be potential AEs.  In one call, the 
consumer reported “Almost swallowed product,” and in the second call the consumer 
reported breaking a molar tooth while chewing on Verve® discs for the first time.  
Overall, based on the information presented, it is anticipated that VBM-FG2 will be well 
tolerated in this study.  
The participants will be made aware of the possible risks associated with the use of the product.  VBM-FG2 
packages will have the following warning: “This product contains tobacco-derived nicotine.  Nicotine is 
addictive.  Nicotine can harm your baby if you are pregnant or nursing.  Nicotine can increase your heart 
rate, blood pressure, and aggravate diabetes.  Nicotine can cause dizziness, nausea and stomach pain.” 
1.2 Rationale  
The current study will serve as a pilot study for a larger study with a similar design.  The 
purpose of this pilot study is to estimate changes in biomarkers of exposure (BOE) in 
adult cigarette smokers using VBM-FG2 discs relative to adult smokers who continue 
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Protocol No: COV-VER-01-13 
 
Issue Date Amendment 1: 20 August 2013 
 
smoking and do not receive VBM-FG2 discs.  Results of this study will be used to 
estimate the sample size for a proposed pivotal study.  Results of this study will also be 
used to determine the optimal method by which to measure product use behavior; daily 
product use tracking via interactive voice response system (IVRS) or weekly product use 
recall.   
2 PURPOSE AND STUDY OBJECTIVES 
2.1 Purpose 
The purpose of this study is to 1) estimate the change in BOE in adult smokers using 
VBM-FG2 versus adult smokers not using VBM-FG2, and 2) determine the appropriate 
CPD reporting method for baseline measurements (for IVRS Baseline is defined as the 
average CPD recorded on Days 2 through 8)  
2.2 Primary Objective 
The primary objective of this study is to: 
• Compare the differences in percent change in urinary total 4-(methylnitrosamino)-
1-(3-pyridyl)-1-butanol (NNAL) from Baseline to End of Study between adult 
smokers randomly assigned to Test Group (ad libitum VBM-FG2 use) and 
Control Group (no VBM-FG2). 
2.3 Secondary Objectives 
The secondary objectives of this study are to: 
• Compare the difference in BOE (urinary total NNAL, nicotine metabolites, 
S-phenylmercapturic acid [S-PMA], blood carboxyhemoglobin [COHb], and 
exhaled carbon monoxide [CO]) and CPD between two methods for determining 
CPD during the Baseline Period: 
o Recall of average daily CPD for prior week using Past 7 Day Cigarettes Use 
Questionnaire (Day 1).  
o Daily CPD tracking using an IVRS (7 day average of values recorded on 
Days 2 through 8).  
• Compare the differences in percent change in urinary nicotine equivalent (NE), 
S-PMA, blood COHb, exhaled CO, and CPD from Baseline to End of Study 
between adult smokers randomly assigned to Test Group (ad libitum VBM-FG2 
use) and Control Group (no VBM-FG2). 
• Compare the changes in all BOE and CPD from Baseline to End of Study 
between Test Group and Control Group over 4 weeks. 
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Protocol No: COV-VER-01-13 
 
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• Characterize subgroups based on change in CPD from Baseline to End of Study 
(no change, <50% reduction, ≥50% reduction, 100% reduction, increase) within 
each study group.  
• Characterize subgroups based on change in total NNAL from Baseline to End of 
Study (no change, reduction, increase) within each study group. 
• Compare changes in the Fagerström Test for Cigarette Dependence from Baseline 
(Day 8) to End of Study within and between each study group 
• Compare changes on the Quit Attempts and Quitting Intentions from Baseline 
(Day 1) to End of Study within and between each study group. 
3 STUDY DESIGN AND EVALUATION 
3.1 Study Design 
This is a randomized, controlled, open-label, parallel group, multi-center, 5-week pilot 
study to determine changes in BOE in adult smokers allowed ad libitum use of 
VBM-FG2 relative to adult smokers who are not allowed use of VBM-FG2.  This study 
will be conducted in approximately 150 adult smokers who are considered to be in over 
all good health.  Subjects will be randomized (based on gender, daily cigarette 
consumption [<20 and ≥20], and quit attempts [any quit attempts/no quit attempts]) to 
Test (allowed VBM-FG2 use) or Control (not allowed VBM-FG2 use) treatment in a 
3:2 ratio (90 subjects randomized to Test: 60 subjects randomized to Control) with no 
more than a 60:40 distribution of either males or females to either group.   
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Protocol No: COV-VER-01-13 
 
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Figure A:  Study Design 
Screening  
Baseline Period*  
Product Use Period†  
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Day -28 to  Day -1 
Day 1 
Day 8±1 
Day 15±1 
Day 22±1 Day 29±1 Day 36±1 
Subject evaluated 
against inclusion and 
exclusion criteria for 
study eligibility  
Baseline CPD data 
gathered using recall 
of previous week and 
daily IVRS call.  
Randomization in a 3:2 ratio (Test:Control) 
• 
Test = ad libitum VBM-FG2 
• 
Control = no VBM-FG2  
 
 
Enrollment 
Randomization 
*Baseline Period = after the daily IVRS call on Day 1 through the daily IVRS call on Day 8.   
†Product Use Period  = after the daily IVRS call on Day 8 through the daily IVRS call on Day 36.  
3.1.1 Duration of Study 
Expected duration of the study, from first subject first visit through last subject last visit 
is approximately 3 months.  Expected duration for each subject is expected to be up to 
approximately 5 weeks (potentially 9 weeks from Screening to End of Study).  All 
subjects will be informed that they are allowed to smoke their own cigarettes or to quit 
smoking during the study.   
3.1.2 Screening 
Screening (Visit 1) will occur within 28 days of Day 1 (Day -28 to Day -1).  An Informed 
Consent Form (ICF) must be signed prior to conducting any study related procedures.  
Potential subjects will undergo an initial evaluation (vital signs, urine pregnancy test 
[females only], and questionnaires) to determine initial eligibility.   
If the Subject passes the initial evaluation, then he/she will be provided with a sample of 
VBM-FG2 and asked to use the product as they like for 15 minutes.  Subjects will then 
complete a Potential Purchase Interest Questionnaire.  If they indicate that they 
“definitely would buy” or “probably would buy” the product on the questionnaire, then 
the subject will undergo the rest of the screening procedures (clinical labs, 
electrocardiogram [ECG]).  Laboratory values will be evaluated by a local laboratory. 
Additional details related to Screening are located in Section 6 (Study Procedures and 
Observations). 
3.1.3 Baseline Period 
Subjects will return to the study site on the evening (between approximately 16:00 and 
19:00) of Day 1 for Visit 2.  A physical examination will be conducted and subjects who 
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Protocol No: COV-VER-01-13 
 
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satisfy all the inclusion criteria and exclusion criteria will be eligible for enrollment in the 
study.   
Once a subject is enrolled in the study (Day 1), if they choose to no longer participate, 
they will be considered a drop-out/early termination subject. 
During the Baseline Period, at Visits 2 and 3 (Days 1 and 8), blood and urine samples 
will be collected for analysis of BOE.  Subjects will also complete the Past 7 Day 
Cigarettes Use Questionnaire (Appendix 5) while at the study site, to indicate their CPD 
over the previous week.   
During the Baseline Period (Days 1 to 8) subjects will report CPD daily through an IVRS 
conducted each day between 16:00 and 19:00.   
At Visit 3, approximately 150 subjects will be randomized to either the Test or Control 
Group in a 3:2 ratio (with not more than a 60:40 distribution of either males or females to 
either group).  VBM-FG2 will be dispensed to subjects randomized to the Test Group for 
ad libitum use beginning after the Day 8 IVRS. 
Additional details related to these visits are located in Section 6 (Study Procedures and 
Observations). 
3.1.4 Product Use Period 
The Product Use Period will begin following the Day 8 ± 1 IVRS and will continue 
through Day 36 ± 1.  Subjects in the Test group will be provided VBM-FG2 for 
ad libitum use.  Subjects in both Test and Control Groups will continue daily tobacco use 
tracking via an IVRS and return to the study site once a week during the 4 week Product 
Use Period for Visits 4 through 7, Days 15, 22, 29, and 36, respectively.   
These weekly visits will include collection of urine and blood samples for BOE 
measurements, dispensing VBM-FG2 supplies (Test Group Only - Days 8, 15, 22, 29) 
and return of VBM-FG2 supplies and collection of empty product packaging (Test Group 
Only - Days 15, 22, 29, 36) as appropriate.  
Subjects will be instructed to report to the Investigator all AEs and changes in 
concomitant medications and if necessary, to return to the study site for further 
evaluation. 
During the End of Study visit (Day 36 or Early Termination), additional assessments will 
be performed to confirm the health and well-being of the subject.   
Additional details related to these visits are located in Section 6 (Study Procedures and 
Observations). 
3.2 Study Population 
Adult cigarette smokers from 21 to 65 years of age, inclusive, will be evaluated for 
possible participation in the study.  Approximately150 subjects will be randomized across 
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Protocol No: COV-VER-01-13 
 
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3 study sites.  Upon written approval from ALCS, study sites may enroll additional 
subjects.  Subjects must satisfy all inclusion and exclusion criteria to be enrolled in the 
study.  
4 SUBJECT SELECTION AND DISCONTINUATION 
4.1 Inclusion 
Subjects must satisfy the following criteria before being enrolled into the study.  Subject 
must: 
 
1) 
sign an Institutional Review Board (IRB)-approved ICF for the study. 
2) 
be between the ages of 21 and 65 years, inclusive, at the time of 
Screening. 
3) 
consumed a minimum of 10 manufactured CPD daily during the last 
6 months (entire 6 month period must have occurred after subject turned 
21 years of age). 
4) 
indicate that he/she smokes cigarettes “every day” at Screening and on 
Day 1 
5) 
be able to fully comprehend the English language. 
6) 
have an active phone number and must have daily access to a touchtone 
phone between 1600 and 1900 hours. 
7) 
be interested in alternative tobacco products to cigarettes at Screening. 
8) 
indicate that they “definitely would buy” or “probably would buy” on the 
VBM-FG2 Potential Purchase Interest Questionnaire. 
9) 
be in generally good health. 
10) 
if female, have a negative urine dipstick pregnancy test. 
11) 
if female heterosexually active and of childbearing potential (i.e., not 
surgically sterile or two years naturally postmenopausal), agree to use a 
medically accepted method of contraception from Screening through the 
End of Study. 
Surgically sterile includes bilateral tubal ligation, essure, hysterectomy, 
or bilateral oophorectomy at least 6 months prior to enrollment.  
Naturally postmenopausal is defined as women having 2 years without 
menses (confirmed by follicle stimulating hormone levels).   
Acceptable methods of contraception are:  (a) hormonal (i.e., oral, 
transdermal patch, implant, or injection) consistently for at least 3 months 
prior to enrollment; (b) double barrier (i.e., condom with spermicide or 
diaphragm with spermicide) consistently for at least 2 weeks prior to 
enrollment and (c) intrauterine device for at least 3 months prior to 
Screening or (d) only have a partner who has been vasectomized for at 
least 6 months prior to enrollment. 
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Protocol No: COV-VER-01-13 
 
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12) 
have clinical laboratory tests within the appropriate reference range or 
which are clinically acceptable to the Investigator. 
13) 
have a negative ethanol, amphetamines, opiates, cannabinoids, and 
cocaine urine drug screen. 
14) 
test negative for human immunodeficiency (HIV), hepatitis B (hepatitis B 
surface antigen [HBsAg]), and Hepatitis C (anti-hepatitis C virus antibody 
[anti-HCV]). 
15) 
be willing and able to comply with the requirements of the study. 
 
4.2 Exclusion 
A subject who meets any of the following exclusion criteria will not be enrolled in the 
study.  Subject must not: 
 
1) 
be pregnant, nursing, or planning to become pregnant during the study 
period. 
2) 
indicate that he/she intends to quit smoking within the next 30 days (at 
Screening or on Day 1).  
3) 
have uncontrolled hypertension, history of coronary heart disease or other 
significant heart conditions, and/or other significant medical conditions 
that might interfere with study procedures. 
4) 
have used prescription anti-diabetic medication and/or insulin therapy 
within 12 months of Day 1. 
5) 
have a history of drug or alcohol abuse within the 24 months prior to 
Screening. 
6) 
have participated in a clinical study for an investigational drug, device, or 
biologic within 30 days prior to enrollment (Day 1). 
7) 
be a current user of nicotine replacement therapy (indicate every day or 
some days on Subject Screener/Tobacco History Questionnaire). 
8) 
be a current or former employee of the tobacco industry or a first-degree 
relative (e.g., parent, sibling, child) of a current or former employee of the 
tobacco industry. 
9) 
have been involved in the development of the study design/conduct or be a 
first-degree relative (e.g., parent, sibling, child) of someone involved in 
the development of the study design/conduct. 
10) 
be a current employee or personnel involved with the study at the study 
site. 
11) 
be currently participating in the study at a different study site (i.e., each 
subject can only be in the study population once). 
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Protocol No: COV-VER-01-13 
 
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4.3 Subject Discontinuation  
Investigators are urged to enroll only those eligible subjects who are likely to complete 
the entire study and who are willing to comply with the protocol-specified procedures.  It 
is the right and duty of the Investigator to interrupt the test product of any subject whose 
health or well-being may be threatened by continuation in this study, or who may be 
experiencing unmanageable factors that may interfere with the study procedures and/or 
the interpretation of study results.  Such subjects will be withdrawn from the study. 
4.3.1 Subject Discontinuation Criteria 
Subject participation in the study may be prematurely discontinued for any of the 
following reasons: 
• Withdrawal of informed consent (subject’s decision and right to withdraw 
at any time for any reason); 
• Any clinical AE, laboratory abnormality, or intercurrent illness, which in 
the opinion of the Investigator, indicates that continued participation in the 
study is not in the best interest of the subject; 
• Failure to comply with protocol requirements; 
• Subjects who become prisoners or become incarcerated; 
• Termination of the study by ALCS; 
• Subjects who are lost to follow-up; 
 
4.3.2 Procedures for Discontinuation 
If a subject discontinues participation in the study, the reason for withdrawal or 
discontinuation will be documented in the case report form (CRF) and source documents.  
End of Study/Early Termination will be performed (see section 6.2.5).  If a subject 
chooses to withdraw from the study because of an AE, the principal specific event and 
any related test results must be captured in the source documents and CRF on both the 
End of Study CRF and the Adverse Event CRF.  Subjects who discontinue participation 
in the study due to an AE experienced during study conduct will, at minimum, be 
followed until resolution, stabilization, or the subject is lost to follow-up.  
If a subject is lost to follow-up, a reasonable effort is required to contact the subject and 
perform the End of Study procedures.  A reasonable effort is considered, at minimum, 
3 phone attempts followed by a certified letter to the subject’s last known address 
requesting their return to the study site for a safety evaluation and return of any test 
product.   
4.3.3 Replacement of Subjects 
Subjects who discontinue early may be replaced at the discretion of the Sponsor.  
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Protocol No: COV-VER-01-13 
 
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5 STUDY CONDUCT 
5.1 Ethics 
This study will be conducted in accordance with the Protocol, Good Clinical Practice 
(GCP) based on the current International Conference on Harmonisation (ICH) guidelines 
for GCP, and the corresponding sections of the United States Code of Federal 
Regulations (CFR) governing the Protection of Human Subjects (21 CFR 50), 
Institutional Review Boards (21 CFR 56), and the Basic Principles of the Declaration of 
Helsinki.   
The study will be conducted in compliance with the protocol.  No deviation(s) from the 
protocol will be implemented without the prior review and approval of the IRB except 
where it may be necessary to eliminate an immediate hazard to a research subject.  In 
such case, the deviation (if applicable to IRB policies) will be reported to the IRB as soon 
as possible.  The protocol, any amendments, and the subject ICF will receive IRB 
approval prior to initiation of the study. 
5.2 Randomization and Administration 
5.2.1  Study Group Assignment (Randomization) 
Each site will be assigned a unique two-digit (e.g. 01, 02, etc.) site number. 
At each site, each subject will be assigned a unique sequential enrollment number 
consisting of “E” + a sequential number beginning with 001 (e.g. E001, E002, E003, 
E004) at enrollment on Day 1.  This enrollment number in combination with the site 
number will remain with the subject until they are randomized on Day 8. 
On Day 8 subjects will be randomized (based on gender, daily cigarette consumption 
[≤20 and >20], and quit attempts [any quit attempt/ no quit attempts]) to either the Test or 
Control Group in a 3:2 ratio (not more than 60:40 distribution of either male or female), 
according to a randomization schedule.  Each subject will be assigned a randomization 
number based on this randomization schedule.  This randomization number will be used 
for identification throughout the study and will not be used for any other subject at the 
study site.  Further details on the randomization will be available in the Randomization 
Specification Plan prepared by Covance and approved by ALCS. 
Because this is an open label study, product use assignments will not be blinded.  
5.2.2 Test Product Administration 
Subjects in the Test Group will be provided VBM-FG2 discs and told to use them 
ad libitum throughout the study.   
5.3 Blinding/Unblinding 
Not applicable.  This study is open label. 
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Protocol No: COV-VER-01-13 
 
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5.4 Prohibited Medications During the Study 
Use of prescription anti-diabetic medication and/or insulin therapy within 12 months of 
Day 1 and throughout the course of the study is prohibited.  Investigational drugs not yet 
approved for their intended use by FDA are prohibited for 30 days prior to Screening and 
throughout the course of the study. 
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Protocol No: COV-VER-01-13 
 
Issue Date Protocol Amendment: 20 August 2013 
 
6 STUDY PROCEDURES AND OBSERVATIONS 
6.1 Time and Events Schedule 
Procedure 
Screening 
Baseline Period 
Product Use Period 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
EOS/ET 
Visit 7 
Day -28 to -1 
Day 1 
Day 8±1 
Day 15±1 
Day 22±1 
Day 29±1 
Day 36± 1 
Obtain Informed Consent 
X 
 
 
 
 
 
 
 
Review Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
Subject Screener/Tobacco History 
X 
 
 
 
 
 
 
 
Identification of Brand of Cigarettes1 
X 
 
X 
X 
X 
X 
X 
X 
Photocopy Cigarette Pack 
X 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
Weight, BMI 
X 
 
 
 
 
 
 
X 
Vital Signs2 
X 
 
X 
X 
X 
X 
X 
X 
Pregnancy Test3 
X 
 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
 
X 
X 
X 
X 
X 
X 
Smoking Cessation Counseling 
X 
 
 
 
 
 
 
X 
Product Trial 
X 
 
 
 
 
 
 
 
Potential Purchase Interest Questionnaire 
X 
 
 
 
 
 
 
X 
ECG4 
 
X 
 
 
 
 
 
X 
Clinical Labs (Chemistry)5 
 
X 
 
 
 
 
 
X 
Clinical Labs (Hematology)6 
 
X 
 
 
 
 
 
X 
Clinical Labs (Urinalysis)7 
 
X 
 
 
 
 
 
X 
HIV, HBsAg, anti-HCV 
 
X 
 
 
 
 
 
 
Urine Drug Screen 
 
X 
 
 
 
 
 
 
Fagerström Test for Cigarette Dependence 
 
 
X 
X 
 
 
 
X 
Past 7 Days Cigarette Use Questionnaire 
 
 
X 
X 
 
 
 
 
Other Tobacco Product Use Questionnaire8 
 
 
X 
X 
X 
X 
X 
X 
Physical Examination 
 
 
X 
 
 
 
 
X 
Quit Attempts and Quitting Intentions Questionnaire – Day 1 
 
 
X 
 
 
 
 
 
Adverse Events9 
 
 
X 
X 
X 
X 
X 
X 
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Protocol No: COV-VER-01-13 
 
Issue Date Protocol Amendment: 20 August 2013 
 
Procedure 
Screening 
Baseline Period 
Product Use Period 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
EOS/ET 
Visit 7 
Day -28 to -1 
Day 1 
Day 8±1 
Day 15±1 
Day 22±1 
Day 29±1 
Day 36± 1 
BOE Analytical Labs (Urine)10  
 
 
X 
X 
X 
X 
X 
X 
BOE Analytical Labs (Blood) 11 
 
 
X 
X 
X 
X 
X 
X 
BOE (Exhaled CO) 12 
 
 
X 
X 
X 
X 
X 
X 
Collection of Banked Urine Sample 
 
 
 
X 
 
 
 
X 
Collection of Banked Blood Sample 
 
 
 
X 
 
 
 
X 
IVRS Product Use Entry13 
 
 
X 
X 
X 
X 
X 
X 
Dispense VBM-FG2 
 
 
 
X 
X 
X 
X 
 
Collect Used/Unused VBM-FG2 packages 
 
 
 
 
X 
X 
X 
X 
Quit Attempts and Quitting Intentions Questionnaire – End 
of Study 
 
 
 
 
 
 
 
X 
Anti-HCV = anti-hepatitis C virus antibody; BMI = body mass index; BOE = biomarker of exposure; ECG = electrocardiogram; EOS = End of Study; ET = 
Early Termination; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; IVRS = Interactive voice Response System 
1 
If a subject’s most commonly used brand of cigarettes has changed, a photocopy will be made of the new preferred brand cigarette pack 
2 
Respiratory rate, pulse rate, blood pressure, and oral temperature; vital sign measurements will be taken with subjects in the sitting position after at least 
10 minutes of rest and at least 15 minutes after the last cigarette smoked 
3 
A urine dipstick pregnancy test will be performed at Screening for all females.  All additional tests pregnancy test will be conducted via serum. 
4 
12-lead ECG (10 electrodes) 
5 
Comprehensive/Complete Metabolic Panel 
6 
Complete Blood Count (CBC) with differential 
7 
Visual examination, chemical examination, microscopic examination 
8 
Other Tobacco Product Use Questionnaire captures the use of tobacco products other than cigarettes and VBM-FG2.   
9 
All AEs occurring after signing of the ICF should be captured in the source and CRF. 
10 
Urine: nicotine and its 5 metabolites (Cotinine, trans-3 '-Hydroxycotinine, trans-3 '- Hydroxycotinine-O-glucuronide, Nicotine-N-glucuronide, and 
Cotinine-N-glucuronide), total NNAL, S-phenyl mercapturic acid, and creatinine 
11 
Blood: carboxy-hemoglobin (COHb) 
12 
Respiratory: exhaled CO 
13 
Daily tobacco product use will be entered into an IVRS between 16:00 and 19:00 (Day 1 through End of Study) 
 
  
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Protocol No: COV-VER-01-13 
 
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6.2 Procedures by Visit 
The Investigator is responsible for adherence to the protocol.  Prompt and complete 
reporting of all pertinent data is essential.  In order to minimize variability of evaluations, 
it is preferred that the same individuals perform the same or similar evaluations for all 
subjects within a site. 
 
6.2.1 Visit 1: Screening (Day -28 to Day -1) 
6.2.1.1 Screening Part 1 
All potential subjects 
• Explain study and obtain signature of informed consent 
• Review inclusion/exclusion criteria 
• Subject Screener/Tobacco History  
• Identification of preferred brand of cigarettes 
• Photocopy cigarette pack 
• Medical history/demographics 
• Height 
• Weight, body mass index (BMI) 
• Vital Signs 
• Urine dipstick pregnancy test (female subjects only) 
• Concomitant medications 
• Product trial 
• Potential Purchase Interest Questionnaire 
• Smoking cessation counseling 
 
6.2.1.2 Screening Part 2 
Only subjects that pass Screening Part 1 
• ECG 
• Chemistry, hematology, urinalysis 
• HIV, HBsAg, anti-HCV Screen 
• Urine drug screen 
 
6.2.2 Visit 2: (Day 1) 
• Past 7 Day Cigarette Use Questionnaire 
• Quit Attempts and Quitting Intentions Questionnaire – Day 1 
• Other Tobacco or Nicotine Containing Product Use Questionnaire 
• Fagerström Test for Cigarette Dependence 
• Vital signs 
• Identification of preferred brand of cigarettes 
• Physical examination 
• Concomitant medications 
• AEs 
• Serum pregnancy test (female subjects only) 
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Protocol No: COV-VER-01-13 
 
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• BOE samples (urine, blood, exhaled CO) 
• IVRS product use daily tracking  
 
6.2.3 Visit 3: Randomization (Day 8 ± 1)  
• Fagerström Test for Cigarette Dependence 
• Past 7 Day Cigarette Use Questionnaire 
• Other Tobacco or Nicotine Containing Product Use Questionnaire 
• Vital signs 
• Identification of preferred brand of cigarettes 
• Concomitant medications 
• AEs 
• Serum pregnancy test (female subjects only) 
• BOE samples (urine, blood, exhaled CO) 
• Collect banked urine, serum and plasma samples 
• Randomization to a Product Use Group (Test or Control) 
• Dispense VBM-FG2 (subjects in Test Group only) 
• IVRS product use daily tracking continues 
 
6.2.4 Visit 4: (Day 15 ± 1), Visit 5: (Day 22 ± 1), Visit 6: (Day 29 ± 1)  
• Other Tobacco or Nicotine Containing Product Use Questionnaire 
• Vital signs 
• Identification of preferred brand of cigarettes 
• Concomitant medications 
• AEs 
• Serum pregnancy test (female subjects only) 
• BOE samples (urine, blood, exhaled CO) 
• Collect used/unused VBM-FG2 packages 
• Dispense VBM-FG2 
• IVRS product use daily tracking continues 
 
6.2.5 Visit 7: End of Study/Early Termination (Day 36 ± 1)  
• Fagerström Test for Cigarette Dependence 
• Other Tobacco or Nicotine Containing Product Use Questionnaire 
• Potential Purchase Interest Questionnaire 
• Quit Attempts and Quitting Intentions Questionnaire – End of Study 
• Smoking cessation counseling 
• Physical examination 
• ECG 
• Chemistry, hematology, urinalysis 
• Vital Signs 
• Identification of preferred brand of cigarettes 
• Weight, BMI 
• Concomitant medications 
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Protocol No: COV-VER-01-13 
 
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• AEs 
• Serum pregnancy test (female subjects only) 
• BOE samples (urine, blood, exhaled CO) 
• Collect banked urine, serum and plasma samples 
• Collect used/unused VBM-FG2 packages 
• IVRS product use daily tracking completes 
 
6.3 Details of Procedures 
The Time and Events Schedule in Section 6.1 summarizes the study procedures to be 
performed at each visit.  Details of the individual study procedures are described below.  
6.3.1 Informed Consent 
All prospective subjects will have the study explained by the Investigator or his/her 
designee. 
All prospective subjects will be required to read, sign, and date the study ICF prior to any 
Screening/study procedures being performed.  Written acknowledgment of the receipt of 
the full informed consent and the subject’s freely tendered offer to participate will be 
obtained from each subject in the study and documented in the source documents.  Each 
subject will receive a signed and dated copy of his/her ICF. 
6.3.2 Height, Weight, and Body Mass Index 
Height (cm) and weight (kg) in indoor clothing with shoes off.  Body mass index will be 
calculated as weight (kg)/height (m) squared.   
6.3.3 Vital Signs 
Vital signs (respiratory rate, pulse rate, blood pressure, oral temperature) should be taken 
in the sitting position after at least 10 minutes of rest and at least 15 minutes after the last 
cigarette smoked. 
6.3.4 Identification of Preferred Brand of Cigarette 
Study site staff will inquire as to a subject’s most commonly used brand of cigarettes at 
each visit.  If the subject’s most commonly used brand changes a photocopy will be taken 
of the new pack. 
6.3.5 Photocopy Cigarette Pack 
Subjects will bring with them a pack of their most commonly used cigarettes.  The pack 
will be color photocopied and the copy will be placed in the source documents.  
6.3.6 Questionnaires 
Self-administered questionnaires will be completed at various times throughout the study 
with a trained study coordinator present for assistance.  The questionnaires to be used in 
this study are as follows and are located in the Appendices: 
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Protocol No: COV-VER-01-13 
 
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• Subject Screener/Tobacco History (history of tobacco use, quit intentions, etc.), 
Visit 1 
• Potential Purchase Interest Questionnaire, Visit 1 and End of Study 
• Fagerström Test for Cigarette Dependence, Visits 2, 3, and End of Study 
• Past 7 Days Cigarette Use Questionnaire, Visits 2 and 3 
• Other Tobacco Product Use Questionnaire, from Visit 2 through End of Study  
• Quit Attempts and Quitting Intentions Questionnaire – Day 1, Visit 2 
• Quit Attempts and Quitting Intentions Questionnaire – End of Study, End of 
Study 
6.3.6.1 Product Trial and Potential Purchase Interest Questionnaire 
Following ICF signature and preliminary check of subject’s well being, vital signs and 
urine pregnancy test (female subjects only), each subject will be instructed that 
VBM-FG2 discs are a new kind of tobacco product designed to appeal to adult smokers 
interested in innovative types of spit-free tobacco product alternatives to cigarettes.  
Adult tobacco product consumers put the product in their mouth, chew on it, and should 
properly dispose of it when they are done.  Subjects will then be provided a single 
VBM-FG2 disc and asked to place the disc in their mouth, chew on it as they like for up 
to 15 minutes, and then remove and discard the disc when done.  After the subject has 
used the product, a Potential Purchase Interest Questionnaire will be administered.  Only 
subjects who meet the non-invasive inclusion/exclusion criteria and indicate that they 
“definitely would buy” or “probably would buy” on the Questionnaire will be allowed to 
continue through the invasive inclusion/exclusion criteria (blood work). 
6.3.7 Medical History/Demographics 
A medical history will be obtained at Screening by the Investigator or qualified designee.  
Medical history and demographic data, including name, sex, age (each subject must show 
proof of age with government-issued identification [e.g., driver’s license] which will be 
photocopied as source documentation), race, tobacco use/history, and smoking history 
will be recorded for each subject. 
6.3.8 Urine Dipstick Pregnancy Tests 
A urine dipstick pregnancy test will be performed at Screening on all female subjects.  
This should be performed and results verified prior to the product trial.   
6.3.9 Concomitant Medications 
Except for medications listed as prohibited, all medications necessary for the health and 
well-being of the subject are permitted.   
At Screening, concomitant medications need to be recorded in the subject’s source 
documents and CRF.  Subjects should be queried at each visit for additions, deletions, or 
modifications to existing concomitant medications.  These changes need to be captured 
throughout the study.   
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Protocol No: COV-VER-01-13 
 
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6.3.10 Inclusion/Exclusion Criteria 
The inclusion and exclusion criteria will be reviewed by the Investigator or qualified 
designee to ensure that the subject qualifies for the study. 
6.3.11 Clinical Laboratory 
All clinical laboratory tests will be conducted by the local laboratory facility accredited 
by the Centers for Medicare and Medicaid Services (Clinical Laboratory Improvement 
Amendments of 1988 [CLIA-88]).  Values for the laboratory parameters are to be within 
the laboratory normal ranges.  Subjects with Screening laboratory values outside the 
normal limits will be accepted into the study only after the Investigator or designee (a 
physician) has determined that the abnormal values are “not clinically significant”. 
Clinical chemistry (comprehensive metabolic panel), hematology (CBC with differential) 
and urinalysis will also be performed at Screening and End of Study.  Comprehensive 
metabolic panel includes, at minimum:  
• General function - glucose, calcium 
• Proteins - albumin, total protein 
• Electrolytes - sodium, potassium, CO2, chloride, 
• Kidney(s) – blood urea nitrogen, creatinine, uric acid 
• Liver – alkaline phosphatase, alanine amino transferase, aspartate amino 
transferase, bilirubin 
Complete blood count with differential will be performed at Screening and End of Study.  
Complete blood count with differential includes, at a minimum: 
• White blood cells (WBC) – neutrophils, eosinophils, basophils, lymphocytes, 
monocytes 
• Red blood cells (RBC) – RBC count, hemoglobin, hematocrit, RBC indices,  
• Platelet count 
Routine clinical urinalysis will be performed at Screening and End of Study/Early 
Termination.  Urinalysis includes, at minimum, bilirubin, blood, glucose, ketones, 
leukocyte esterase, nitrite, pH, protein, specific gravity, and urobilinogen.  Microscopic 
examination will be conducted if protein, leukocyte esterase, nitrite and/or blood are 
detected.  Microscopic analysis will include RBC, WBC, casts, and bacteria.  
6.3.12 Physical Examination 
The Investigator (or qualified designee, which in this instance should be a physician, 
licensed physician’s assistant, or nurse practitioner) will perform a physical examination 
on Day 1 and at End of Study.  A general physical examination includes observations and 
questioning by the Investigator or his/her designee. 
Note: Only Investigators licensed to conduct physical examinations are approved to 
perform physical examinations and must be listed on the Site Signature and Delegation of 
Duties Log. 
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Protocol No: COV-VER-01-13 
 
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6.3.13 ECG 
A 12-lead ECG (10 electrodes) will be performed after at least 5 minutes of rest at 
Screening and End of Study. 
6.3.14 Human Immunodeficiency Virus, Hepatitis B, and Hepatitis C 
Screen  
Human immunodeficiency virus antibody, HbsAg, and anti-HCV screens will be 
performed at Screening. 
6.3.15 Urine Drug Screens 
Urine drug screens will be performed at Screening for ethanol, amphetamines, opiates, 
cannabinoids, and cocaine. 
6.3.16 Serum Pregnancy Tests  
A serum pregnancy test will be performed at all visits subsequent to Screening on all 
female subjects. 
6.3.17 Adverse Events 
Adverse events will be captured from ICF signing.  Subjects should be queried at each 
visit for any additional AEs or modifications to existing events.  These changes need to 
be captured throughout the study.   
6.3.18 Analytical Laboratory (Biomarkers of Exposures) 
Urine BOE (with the exception of creatinine) will be analyzed using validated analytical 
methods with appropriate quality controls according to the FDA Guidance for Industry: 
Bioanalytical Method Validation (May, 2001) and in accordance with FDA Good 
Laboratory Practice regulations (Title 21 CFR Part 58; Laboratory To Be Determined 
[TBD]).  Urine creatinine and blood COHb will be analyzed at a CLIA-88 certified 
clinical laboratory (TBD).  The specific information on the laboratories will be included 
in a Letter of Administrative Change. 
Biomarkers of exposure will include: 
Urine: nicotine and its 5 metabolites (Cotinine, trans-3 '-Hydroxycotinine, trans-3'-
Hydroxycotinine-0-glucuronide, Nicotine-N-glucuronide, and Cotinine-N-glucuronide), 
total NNAL, urinary S-PMA, and creatinine.  
Blood: COHb 
Respiratory: exhaled CO  
6.3.18.1 Urine Sample Collection for Biomarker Analysis 
A urine sample will be collected at Visits 2 through 7.  Urine will be collected upon 
arrival at the study site.  Participants will be instructed to not void their bladders for 
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Protocol No: COV-VER-01-13 
 
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approximately 2 hours before the study visit.  The total volumes for each urine void will 
be recorded. 
Briefly, aliquots (in the order of priority) will be prepared according to Table A for each 
subject.  All aliquots will be prepared and then stored at -70°C or lower until analyzed or 
shipped.  The additional back-up sample may be used for potential re-assays of BOEs and 
will be stored until the Clinical Study Report is finalized. 
Table A:  Samples for Analysis of Urinary Biomarkers of Exposure 
Urine Biomarkers 
Number of 
Aliquots 
Aliquot 
volume (mL) 
Total Volume for 
Parameter (mL) 
Container 
Type 
Total NNAL 
2 
10 
20 
TBD 
Nicotine Equivalents 
2 
5 
10 
TBD 
S-PMA 
2 
5 
10 
TBD 
Creatinine 
2 
5 
10 
TBD 
Additional Back-up Sample  
1 
50 
50 
TBD 
Banked Sample 
1 
50 
50 
TBD 
 
6.3.18.2 Blood Sample Collection for Biomarker Analysis 
Blood sample collections for analytical labs will be collected at Visits 2 through 7.  Blood 
samples should be collected after urine collection following vital sign measurements.  
Subject visits should be scheduled such that blood samples can be collected as late in the 
day as possible and preferably at the same or similar time with each visit.   
A 4-mL blood sample for COHb analysis will be drawn in sodium heparin (green top) 
vacutainer tubes.  Immediately following collection, the blood samples will be gently 
inverted and refrigerated.  The whole blood samples will be properly labeled and 
delivered to the laboratory. An additional 2 samples of blood (1 for serum [5 mL] and 
1 for EDTA/plasma [4 mL]) will be collected at Visit 3 and again at End of Study for 
sample banking.  Details on blood sample volumes for BOE analysis, clinical laboratory 
evaluations, and serology are noted in Table B. 
Table B:  Blood Sample Volumes 
Parameter 
Maximum Blood 
Volume Per Sample 
(mL) 
Approximate 
Number of Blood 
Samples 
Approximate Total 
Blood Volume 
Hematology 
4 
2 
8 
Chemistry 
8.5 
2 
17 
HIV, HBsAg, anti-HCV 
8.5 
1 
8.5 
COHb 
4 
6 
24 
Sample Banking – Serum 
5 
2 
10 
Sample Banking – Plasma 
4 
2 
8 
Serum Pregnancy 
8.5 
6 
51 
Total 
Male 
75.5 
Female 
126.5 
 
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6.3.18.3 Sample Banking 
Samples of urine and blood (serum and EDTA/plasma) will be collected at Visit 3 and 
End of Study, and stored for up to 1 year for possible future exploratory analysis (details 
of processing and storage are contained in a separate document).  Each subject will give 
consent for the collection of samples for banking.   
6.3.18.4 Exhaled CO Measurement 
Exhaled CO measurement tests should occur immediately after blood collection. A 
standard exhaled CO Test will be performed with Micro+™ Smokerlyzer® CO monitors 
(or equivalent) following the manufacturer’s instructions.   
6.3.19 Interactive Voice Response System 
Interactive Voice Response System is a tool which uses a telephone as a device to input 
information.  It is an entirely automated and user-friendly system.  To utilize the IVRS, a 
study subject will call into a pre-specified number and answer recorded questions using 
the number pad on a touch tone phone. 
 
In this study an IVRS will be used between 16:00 and 19:00 on Days 1 to 36 to assess 
CPD.  The IVRS assessment on Day 1 will serve as orientation to the system.  Subjects 
will be instructed to call into the system and to answer a preset sequence of questions.  
During the Baseline Period, the same questions will be asked of every subject.  Following 
randomization, beginning on Day 9, subjects assigned to the Control Group will continue 
to answer the same set of questions administered during the Baseline Period.  Subjects 
randomized to the Test Group will be asked the same questions that were asked during 
the Baseline Period, as well as an additional 2 questions related to VBM-FG2 
consumption. 
6.3.20 Smoking Cessation Counseling 
The Investigator or designee, at Screening and at the end of the Study or upon Early 
Termination, will advise all adult smokers that to reduce the health effects of smoking 
and using smokeless tobacco products, the best thing to do is to quit.  The Investigator or 
designee will also offer all adult smokers the Quit Assist™ brochure and refer all adult 
smokers to the Quit Assist™ website, which contains citations to a number of third-party 
information sources, including websites, telephone resources, and other organizations 
with additional information.  
7 CLINICAL SUPPLIES 
7.1 Test Product 
The test product consists of open-label, child resistant tubular packaged VBM-FG2 discs.  
The VBM-FG2 discs are mint-flavored, non-dissolving, discs that contain approximately 
1.5 mg of nicotine.  The amount of nicotine a subject actually receives depends on how 
he or she uses the product (e.g., how many discs are chewed, how hard they are chewed, 
and how long they are chewed or kept in the mouth).   
 
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7.2 Packaging and Labeling 
The VBM-FG2 discs will be provided to subjects in a child resistant tubular container 
(16 discs within each tube). 
 
The label has black letters on a white background.  Stating: 
Tobacco Product 
Consumer Test Product.  Not for Sale. 
Warning: This product contains tobacco-derived nicotine.  Nicotine is addictive.  
Nicotine can harm your baby if you are pregnant or nursing.  Nicotine can increase your 
heart rate, blood pressure, and aggravate diabetes.  Nicotine can cause dizziness, nausea 
and stomach pain. 
Distributed by Product Opinion Laboratory  
Richmond VA 23261 
The packaging also has a sticker indicating the product is VBM-FG2 and the date 
manufactured. 
Prior to dispensing, the site will apply a label to disclose, at minimum, the protocol 
number and unique subject identifiers, date it was dispensed, and a statement to “keep out 
of reach of children”.   
7.3 Storage, Handling and Dispensing 
Altria Client Services, Inc. will be responsible for assuring that the quality of the test 
product provided is adequate for the duration of the trial.  Test products should be stored 
under room temperature [15 to 25°C (59 to 77°F)] conditions in a locked limited-access 
area.   
The test product shall be dispensed in accordance with the protocol.  Test product must 
be dispensed only from IRB-approved protocol-specific study sites.  The product must 
only be dispensed by the Investigator or designee documented on the Site Signature and 
Delegation of Duties Log.   
Subjects in the Test Group will initially receive 7 tubes of VBM-FG2 at Visit 3.  Subjects 
will be asked to bring back all product packages (empty, partially used, unopened) and 
unused product at each subsequent study visit.  Study sites will perform accountability on 
the returned product and tailor future dispensation numbers based on product use.  If a 
subject has used more than 6 of the 7 tubes received, an additional 3 tubes will be 
dispensed for the next week (up to a maximum of 12 tubes in 1 week).  At subsequent 
visits, additional tubes will be dispensed in the same manner (if 9 of the 10 tubes are 
used, 12 tubes will be given).  Otherwise subjects will receive the same amount 
(7 unopened tubes per week).  Subjects will be instructed that they should not use more 
than 24 discs per day.  Unused tubes will be re-dispensed to the same subject. 
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Only unused tubes with the tamper evident seal intact should be dispensed to the subject. 
During product dispensing, subjects will be reminded to keep the product out of reach of 
children. 
The subjects will be instructed to store the containers in a cool dry place and not to leave 
the container(s) in extreme conditions (e.g. in a car parked in the heat/cold, freezer, etc). 
7.4 Test Product Records at Study Sites 
It is the responsibility of the Investigator to ensure that a current record of test product 
accountability is maintained at each study site where test product is inventoried and 
dispensed.  Records or logs must include: 
• Amount received/placed in storage area 
• Amount dispensed to and returned by each subject, including unique subject 
identifiers 
• Non-study disposition (e.g., lost, wasted, broken) 
• Amount returned to Sponsor 
• Amount destroyed at study site, if applicable 
• 10 tubes of VBM-FG2 will be retained by each study site until final Clinical 
Study Report is issued  
7.5 Return and Destruction of Test Product 
7.5.1 Return 
Upon completion or termination of the study, all unused and/or partially used test product 
must be returned to Altria Client Services, Inc. or designee, if not authorized by ALCS to 
be destroyed at the study site. 
All test products returned to Altria Client Services, Inc. or designee must be accompanied 
by the appropriate documentation and be clearly identified by protocol number and site 
number on outermost shipping container.  Returned supplies should be in the original 
containers (e.g., tubes that have clinical labels attached).  Empty containers should not be 
returned to Altria Client Services, Inc.  It is the Investigator’s responsibility to arrange for 
disposal of all empty containers, provided that procedures for proper disposal have been 
established according to applicable federal, state, local, and institutional guidelines and 
procedures and provided that appropriate records of disposal are kept.  The responsible 
ALCS Contact (or designee) should arrange the return of unused test product(s). 
7.5.2 Destruction 
If written authorization to destroy test product has been issued by Altria Client Services, 
Inc. to a study site, it is the Investigator’s responsibility to ensure that arrangements have 
been made for the disposal, according to applicable regulations, guidelines, and 
institutional procedures.  Appropriate records of disposal must be documented.  The 
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unused test products can only be destroyed after being inspected and reconciled by the 
responsible ALCS Contact (or designee). 
8 ADVERSE EVENT REPORTING IN CLINICAL TRIALS 
8.1 Adverse Events 
The following is the definition for an AE: 
Any unfavorable and unintended sign (including an abnormal laboratory 
findinga), symptom, or diseaseb temporally associated with the use of a study 
product, whether or not related to the study product.2,3 
a For this study, a laboratory AE is defined as an abnormal laboratory finding that is 
determined by the Investigator to be clinically significant for that subject. 
b This includes a newly developed, worsened preexisting, recurring intermittent or intercurrent 
illness, injury, or condition. 
All AEs occurring during this clinical trial after the subject has signed the ICF document 
must be recorded in the CRF, including the date and time of onset and outcome of each 
event.  Events captured between Screening (Visit 1) and Visit 2 occurring prior to study 
product usage will be documented as baseline signs and symptoms and not AEs, unless 
“likely” or “definitely” associated with product trial use in Screening Part 1. 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions 
that require surgery.  The condition for which the surgery is required may be an AE.  
Planned surgery permitted by the clinical study protocol and the condition(s) leading to 
this surgery are not AEs. 
No causal relationship with the study products or with the clinical study itself is implied 
by the use of the term “adverse event.” 
The Investigator will review each event and rate each reported sign or symptom on a 
3-point severity scale.  The following definitions for rating severity2 will be used: 
Mild: 
The AE is easily tolerated and does not interfere with daily 
activity. 
Moderate: 
The AE interferes with daily activity, but the subject is still 
able to function. 
Severe: 
The AE is incapacitating and requires medical intervention.  
Note: This is not the same as “serious,” which is based 
on the outcome or action criteria usually associated with 
events that pose a threat to life or functioning.   
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Each AE will also be assessed by the Investigator for relationship to study product 
(causality) using the following grades of certainty4,5 (the strength of a causal association 
may be revised as more information becomes available): 
Not related:   
Clearly and definitely due to extraneous cause (e.g., disease, environment) 
Unlikely:  
 
a. 
Does not follow a probable temporal (i.e., time) sequence from use of 
study product. 
b. 
Does not follow a known pattern of response to the study product. 
c. 
Could plausibly have been produced by the subject’s clinical 
state/underlying disease or other drugs or chemicals the subject received. 
d. 
Does not reappear or worsen when the study product is re-administered. 
Possible: 
 
a. 
Follows a reasonable temporal (i.e., time) sequence from use of study 
product 
b. 
Follows a known pattern of response to the study product. 
c. 
Could also have been produced by the subject’s clinical state/concurrent 
disease or other drugs or chemicals the subject received. 
Likely:   
a. 
Follows a reasonable temporal (i.e., time) sequence from use of study 
product. 
b. 
Follows a known pattern of response to the study product. 
c. 
Could not readily have been produced by the subject’s clinical 
state/concurrent disease or other drugs or chemicals. 
d. 
Follows a clinically reasonable response on withdrawal (dechallenge), 
i.e., disappears or decreases when the study product is stopped or 
reduced. 
e. 
Rechallenge information is not required to fulfill this definition. 
Definitely: 
 
a. 
Follows a reasonable temporal (i.e., time) sequence from use of study 
product. 
b. 
Follows a known pattern of response to the study product. 
c. 
 Cannot be explained by the subject’s clinical state/concurrent disease or 
other drugs or chemicals. 
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d. 
Follows a clinically reasonable response on withdrawal (dechallenge), 
i.e., disappears or decreases when the study product is stopped or 
reduced. 
e. 
Recurs with re-exposure to study product (rechallenge).  NOTE: 
Re-exposure of the subject is NOT required, but the “certainly/definitely 
related” category may only be used when recurrence is observed. 
8.2 Serious Adverse Events 
The following is the definition for a serious adverse event (SAE): 
An SAE is any adverse study experience that results in any of the following outcomes:   
• 
death 
• 
a life-threatening adverse study experiencea 
• 
in-patient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant disability/incapacityb  
• 
a congenital anomaly/birth defect.3 
a “Life-threatening” means that the subject was at immediate risk of death at the time of 
the SAE; it does not refer to a SAE that hypothetically might have caused death if it 
were more severe. 
b “Persistent or significant disability/incapacity” means that there is a substantial 
disruption of a person’s ability to carry out normal life functions. 
Important medical events that may or may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse study experience when, based upon appropriate medical judgment, it 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.  An example is allergic bronchospasm requiring intensive treatment in an 
emergency room or at home. 
All SAEs, whether or not considered study-related, must be reported by telephone and by 
fax to the Sponsor within 24 hours of the site’s learning of the SAE or, at the latest, on 
the following workday.  The Sponsor’s representative to contact about this study is: 
Jianmin Liu, M.D. 
Clinical Quality Assurance Manager 
Altria Client Services Inc. 
601 E. Jackson Street 
Richmond, Virginia  23119 
Phone: (804) 335-2441 
Cellular: (804) 852-4156 
Fax: (804) 335-2300 
 
The Investigator must also inform the IRB, in compliance with GCP reporting guidelines, 
and the site monitor of an SAE, whether or not considered study-related.  The initial 
report must be as complete as possible, including an assessment of the causal relationship 
between the event and the study product.  Information not available at the time of the 
initial report (e.g., end date, laboratory values) must be documented on a follow-up SAE 
form. 
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8.3 Adverse Event/Serious Adverse Event Follow-Up 
Each AE including clinically significant laboratory abnormalities, whether serious or 
non-serious, will be followed to a final outcome regardless of whether the subject is still 
participating in the study.  Final outcome may be classified as resolved, improved, 
unchanged, worse, fatal, or unknown (lost to follow-up).  Where appropriate, medical 
tests and examinations will be performed to document the outcome of the AE. 
8.4 Pregnancy 
Pregnancy occurring in a female study subject during the study will be documented in a 
note to file and as a protocol deviation in the clinical conduct study report to the IRB.  
Pregnancy itself is not a SAE.  The Investigator or designee will discontinue the pregnant 
subject from the study and will advise her to seek prenatal care and counseling from her 
primary care provider.  If the pregnant subject smokes, the Investigator will offer her a 
Quit Assist™ brochure and refer her to the Quit Assist™ website, which contains 
citations to a number of third-party information sources, including websites, telephone 
resources and other organizations with additional information.  Advice given will be 
documented in the subject’s source document. 
The site clinical staff will request the pregnant subject to notify the site of the outcome of 
the pregnancy (i.e., birth, loss, or termination).  To help ensure this, the site clinical staff 
will follow up with the subject until the end of pregnancy, if in compliance with the site’s 
standard operating procedures and with the subject’s consent.  This request and the 
subject’s response will be documented in the subject’s source document. 
9 Data Management 
Every effort will be made to ensure that data management practices adhere to 
international ethical and scientific quality standard of clinical data management 
procedures.  The sponsor will select and contract with a contract research organization 
(CRO) to maintain the database for this investigation.   
9.1 Database Design and Creation 
An appropriate database will be designed and created within a validated Clinical Data 
Management System (CDMS).  This database will be designed to store the data as 
recorded on the CRFs and will ensure a one-to-one mapping between the CRFs and the 
electronic copy stored in the system. 
9.2 Data Coding 
Upon completion of CRF data entry by the CRO, a secondary, in-house clinical review 
will be conducted.  Adverse event coding will be undertaken using Medical Dictionary 
for Regulatory Activities.  This version of the dictionary will remain the same throughout 
the trial. 
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9.3 Data Entry and Verification 
The data recorded on the CRFs will be entered via independent, double data entry into the 
CDMS. 
9.4 Study Results Data Transfer 
Study data transfers will be sent to ALCS, or their designee, electronically on a schedule 
and in a format mutually agreed upon by ALCS or their designee, and the vendor 
responsible for the analysis of these study data.   
9.5 Data Validation 
After the data have been entered and verified, various edit checks will be performed to 
ensure the accuracy, integrity and validation of the database against the CRFs. 
Inconsistencies that arise from these edit checks will be resolved with the Investigator or 
designee. 
9.6 Database Lock 
On completion of the trial, after data entry is complete and the data has been pronounced 
clean, the database will be locked and final write access will be removed. 
A data management plan will be created to describe the details of the data management. 
10 STATISTICS 
10.1 Sample Size Determination 
This pilot study is being conducted with the objective to collect data on the variability of 
the primary outcome measure, which will be used to estimate the sample size for a future 
pivotal study.  The sample size for this study is believed to be appropriate based on 
statistical principles for pilot studies.  
10.2 Criteria for Evaluation 
10.2.1 Primary Outcome Measure (Endpoints) 
The primary outcome measure is: 
• Differences in the percent change from Baseline to the End of Study in urinary 
total NNAL between Test and Control Groups. 
 
10.2.2 Secondary Outcome Measures (Endpoints) 
The secondary outcome measures are: 
• Differences in all BOE during the Baseline Period between Day 1 (weekly recall) 
versus Day 8 (daily tracking using IVRS).  
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• Difference in CPD during the Baseline Period between once weekly recall 
(Days 1 and 8) versus daily tracking (average of recordings on Days 2 through 8). 
• Differences in the percent change from Baseline to End of Study in BOE (urinary 
NE , S-PMA, blood COHb, exhaled CO) and CPD between the Test and Control 
Groups. 
• Differences from Baseline to End of Study in all BOE and CPD between the Test 
and Control Groups. 
• Proportion of subjects in subgroups based on cigarette consumption change from 
Baseline to End of Study (no change, <50% reduction, ≥50% reduction, 100% 
reduction, increase) within and between the Test and Control Groups. 
• Proportion of subjects in subgroups based on total NNAL change from Baseline 
to End of Study (no change, reduction, increase) within each group. 
• Changes from Baseline (Day 8) to End of Study in Fagerström Test for Cigarette 
Dependence, within and between the Test and Control Groups.  
• Changes from Baseline (Day 1) to End of Study on the Quit Attempts and 
Quitting Intentions, within and between the Test and Control Groups. 
10.2.3 Safety Outcome Measures (Endpoints) 
Safety analyses will be conducted on the safety population.  Safety analyses will include 
summaries and analysis of AEs as well as summaries of vital signs and laboratory test 
results. 
See Section 8 for details of procedures for assessment and reporting of AEs. 
10.3 Data Set Descriptions 
Intent to treat (ITT) population includes every subject who is randomized according to 
the randomization schedule. 
Per-protocol (PP) population is defined as a subset of the ITT population which is 
comprised of subjects who completed the study without any major protocol violations. 
10.4 Data Set Analyses 
Both the ITT and the PP populations will be used in the statistical analyses.   
Gender, average daily cigarette consumption (≤20 and >20) and quit attempts may affect 
the primary outcome of the study and they will be considered in the randomization.  A 
randomization plan will be developed to balance these factors between the product use 
groups.  Other factors such as study site, socio-economic status, etc., will be adjusted in 
statistical analyses.  The details of the plan will be provided in the statistical analysis 
plan.   
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Deviations from the approved statistical analysis plan will be reported in the final study 
report.   
10.4.1 Demographics and Baseline Characteristics 
Demographic baseline characteristics will be summarized by product use group with 
descriptive statistics (the number of non-missing values, mean, median, standard 
deviation [SD], minimum, maximum, CV, 95% confidence interval [CI]) for continuous 
variables (e.g., BMI) and frequency counts for categorical variables (e.g., gender).  
Fisher’s exact test will be used to test for the differences in categorical variables between 
the two study groups and t test, to test for the differences in continuous variables. 
10.4.2 Endpoint Analyses 
All descriptive and inferential statistical analyses will be performed using SAS software 
version 9.3. 
10.4.2.1 Primary Endpoint Analyses 
A linear mixed model for repeated measures analysis of variance will be used for the 
analyses of the primary outcome measure.  Terms of the model will be defined in the 
statistical analysis plan.  SAS procedure Proc Mixed will be used for the statistical 
computing.  
10.4.2.2 Secondary Endpoint Analyses 
For the secondary outcome measures with a difference over time, a linear mixed model 
for repeated measures analysis of variance will be used for the analysis of the secondary 
outcome measure.  The model will include terms for study group and/or cigarette tracking 
method, study time, and subject.  SAS procedure Proc Mixed will be used for the 
statistical computing. 
For correlations, a linear regression analysis will be conducted to examine the 
relationships between levels of biomarkers (dependent variable) with either the weekly 
cigarette counts (independent variable) or the daily cigarette counts.  The coefficients of 
determination will be compared. 
For proportion of subjects, The Mantel-Haenszel Chi-Square Test will be used to test the 
frequency differences between the two groups. 
10.4.3 Safety Data Analyses 
A by-subject AE data listing, including verbatim term, preferred term, study product, 
severity, and relationship to study product, will be provided. 
The number of subjects experiencing AEs and the number of AEs will be summarized by 
study group using frequency counts. 
Descriptive statistics will be calculated for quantitative safety data and frequency counts 
will be compiled for classification of qualitative safety data.  
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Changes in physical examinations will be described in the text of the final report. 
10.4.4 Interim Analyses 
An interim data analysis will be conducted after the first 50 subjects (approximately 
30 Test Group and 20 Control Group subjects) have completed the study.  The analysis 
will be based on data from the 50 subjects up to the completion time point. 
The purpose of the analysis is to obtain timely information for the planning of a proposed 
pivotal study.  Descriptive statistics (n, mean, median, SD, range, 95% CI) will be 
provided by study group for subject demographics, the primary endpoint variable, and the 
secondary endpoint variables that are continuous in scale.  Frequency distribution 
(number and proportion) will be provided for the safety variables and the secondary 
endpoint variables that are categorical.  
10.5 Accounting for Missing, Unused, and Spurious Data 
No imputations will be made for missing safety data. 
11 QUALITY ASSURANCE 
11.1 Compliance with Protocol and Protocol Revisions 
The study shall be conducted as described in this approved protocol.  All revisions to the 
protocol must be discussed with, and be prepared by, ALCS or designee.  The 
Investigator should not implement any deviation or change to the protocol without prior 
review and documented approval from the IRB of an Amendment, except where 
necessary to eliminate an immediate hazard(s) to study subjects.  Any significant 
deviation must be documented.   
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) 
prior to obtaining IRB approval, as soon as possible the deviation or change will be 
submitted to: 
• IRB for review and approval; 
• ALCS; 
• Regulatory Authority(ies), if required. 
Documentation of approval signed by the chairperson or designee of the IRB(s) must be 
sent to ALCS. 
If an Amendment substantially alters the study design or increases the potential risk to the 
subject:  (1) the consent form must be revised and submitted to the IRB(s) for review and 
approval; (2) the revised form must be used to obtain consent from subjects currently 
enrolled in the study if they are affected by the Amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment. 
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11.2 Monitoring for Protocol Compliance 
Altria Client Services, or designee, must be allowed to visit all study site locations 
periodically to assess the data quality and study integrity.  On-site they will review study 
records in comparison with source documents, discuss the conduct of the study with the 
Investigator, and verify that the facilities remain acceptable.   
In addition, ALCS internal auditors and government inspectors may evaluate the study 
and must be allowed access to CRFs, source documents and other study files.  Altria 
Client Services audit reports will be kept confidential. 
Additional information regarding protocol specific monitoring procedures is maintained 
by ALCS, external to the protocol.   
THE INVESTIGATOR MUST NOTIFY ALCS PROMPTLY OF ANY INSPECTIONS 
SCHEDULED BY REGULATORY AUTHORITIES, ALLOW ALCS TO BE 
PRESENT AND PROMPTLY FORWARD COPIES OF INPECTION REPORTS TO 
ALCS. 
12 ETHICAL AND LEGAL CONSIDERATIONS 
12.1 Institutional Review Board 
Before study initiation, the Investigator must have written and dated approval from the 
IRB for the protocol, ICF, subject recruitment materials/process (e.g., advertisements), 
and any other written information to be provided to subjects.  The IRB approval should 
be obtained in writing, clearly identifying the trial, the documents reviewed, and the date 
of the review.   
As appropriate, amendments to the above stated documents must also be submitted and 
receive approval from the IRB prior to implementation at the study site.  The IRB 
approval should be obtained in writing, clearly identifying the trial, the documents 
reviewed, and the date of the review.   
The Investigator or Sponsor should also provide the IRB with a copy of any product 
labeling, reports, updates and other information according to regulatory requirements or 
Institution procedures. 
12.2 Informed Consent 
Investigators must ensure that subjects are clearly and fully informed about the purpose, 
potential risks and other critical issues regarding clinical trials in which they volunteer to 
participate. 
12.2.1 Informed Consent Procedures 
Preparation of the consent form must include all elements required by ICH, GCP and 
applicable regulatory requirements, and must adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.  The consent form must also include a 
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statement that ALCS and regulatory authorities have direct access to subject records.  
Prior to the beginning of the study, the Investigator must have the IRB’s written approval 
of the written ICF and any other information to be provided to the subjects. 
The Investigator must provide the subject with a copy of the consent form and written 
information about the study in the language in which the subject is most proficient.  The 
language must be non-technical and easily understood.  The investigator should allow 
time necessary for subject to inquire about the details of the study, then informed consent 
must be signed and personally dated by the subject and by the person who conducted the 
informed consent discussion.  The subject should receive a copy of the signed informed 
consent and any other written information provided to study subjects prior to subject’s 
participation in the trial. 
12.2.2 Update of Informed Consent 
The informed consent and any other information provided to subjects, should be revised 
whenever important new information becomes available that is relevant to the subject’s 
consent, and should receive IRB approval prior to use.  The Investigator, or a person 
designated by the Investigator should fully inform the subject of all pertinent aspects of 
the study and of any new information relevant to the subject’s willingness to continue 
participation in the study.  This communication should be documented. 
12.3 Confidentiality 
12.3.1 Confidentiality of Data 
By signing this protocol the Investigator affirms to ALCS that information furnished to 
the Investigator by ALCS will be maintained in confidence and such information will be 
divulged to the Institutional Review Board, Ethical Review Committee, or similar or 
expert committee, affiliated institution, and employees only under appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this study will be considered confidential by the 
Investigator.   
12.3.2 Confidentiality of Subject Records 
The confidentiality of records that could identify subjects must be protected, respecting 
the privacy and confidentiality rules in accordance with the applicable regulatory 
requirement(s).  By signing this protocol the Investigator agrees that ALCS (or Sponsor 
representative), IRB, or Regulatory Agency representatives may consult and/or copy 
study documents in order to verify CRF data.  By signing the consent form, the subject 
agrees to this process.  If study documents will be photocopied during this process of 
verification, the subject will be identified by unique code; full name and other personal 
identifiers will be masked.6 
12.3.3 Confidentiality of Investigator Information 
By signing this protocol the Investigator recognizes that certain personal identifying 
information (e.g., name, hospital or clinic address, curriculum vitae) may be made part of 
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Protocol No: COV-VER-01-13 
 
Issue Date Amendment 1: 20 August 2013 
 
a regulatory submission and may be transmitted (either in hard copy or electronically) to 
ALCS for internal study management purposes or as required by individual regulatory 
agencies.  Additionally, the Investigator’s name, hospital/clinic address/phone number 
may be included when reporting certain SAEs to other investigators and stored in 
managed regulatory-controlled databases. 
13 ADMINISTRATIVE 
13.1 Records and Reports 
An Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the investigation on each 
individual treated with the test product or entered as a control in the investigation.  Data 
reported on the CRF that are derived from source documents, must be consistent with the 
source documents or the discrepancies must be explained. 
The CRF must be completed legibly in ink.  Subjects are to be identified by initials, date 
of birth, and subject number, if applicable.  All requested information must be entered on 
the CRF in the spaces provided.  If an item is not available or is not applicable, it must be 
documented as such; do not leave a space blank. 
The Investigator will maintain a Site Signature and Delegation of Duties Log to 
document signatures and initials of all persons authorized to make entries and/or 
corrections on the CRFs.  A correction must be made by striking through the incorrect 
entry with a single line and entering the correct information adjacent to the incorrect 
entry.  The correction must be initialed and dated by the person making the correction 
and must not obscure the original entry.  The source documents may further provide an 
explanation for the change, if necessary. 
The completed CRF must be promptly reviewed, signed and dated by a qualified 
investigator or sub-investigator.  The Investigator must retain a copy of the CRFs 
including records of the changes and corrections. 
13.2 Records Retention 
The Investigator must maintain copies of all documents and records related to the 
conduct of the trial (such as test product disposition records, copies of CRFs (or 
electronic files), and source documents, etc.) for the maximum period required by 
applicable regulations and guidelines, or Institution procedures, or for the period 
specified by ALCS, whichever is longer.  At a minimum, trial records must be retained 
for at least 2 years after the last approval/authorization of a marketing application or at 
least 5 years have elapsed since the formal discontinuation of clinical development of the 
test product.   
If the Investigator wishes to relocate the records or is unable to retain them for the 
specified retention period, ALCS must be contacted and notified in writing. 
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Protocol No: COV-VER-01-13 
 
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If the Investigator withdraws from the study (e.g., relocation, retirement) the records shall 
be transferred to a mutually agreed upon designee (e.g., another investigator, IRB).  
Altria Client Services must be notified in writing of any such transfer.   
All trial documents shall be made available if required by relevant health authorities.  The 
Investigator must contact ALCS prior to destroying any records associated with the 
study. 
13.3 Sponsor 
The sponsor of this study is: 
Altria Client Services, Inc. 
P.O. Box 26583 
Richmond, VA  23261-6583 
13.4 Investigators, Study Sites, and Institutional Review Boards 
Only investigators qualified by training and experience to perform a clinical investigation 
with a test product are selected.  Altria Client Services or designee will contact and select 
all principal investigators (legally responsible party[ies] at each study site), who, in turn, 
will select their staff.  
A list of active Investigator names, sub-investigator names, Institution names/addresses 
and reviewing IRBs names/addresses is maintained by ALCS, external to the protocol.   
13.5 Central Organizations and/or Vendors 
A list of names and addresses of organizations and/or vendors involved in subject 
management and associated testing and analysis where it affects the validity of the 
investigation is maintained by ALCS, external to the protocol.
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Protocol No: COV-VER-01-13 
 
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14 GLOSSARY OF TERMS AND LIST OF 
ABBREVIATIONS 
14.1 List of Abbreviations 
 
Term 
Definition 
AE 
Adverse event 
ALCS 
Altria Client Services 
anti-HCV 
Anti-hepatitis C virus antibodies 
BMI 
Body mass index 
BOE 
Biomarkers of exposure 
°C 
Degrees Celsius 
CBC 
Complete blood count 
CDMS 
Clinical Data Management System 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CLIA-88 
Clinical Laboratory Improvement Amendments of 1988 
CO 
Carbon monoxide 
COHb 
Carboxyhemoglobin 
CPD 
Cigarettes per day 
CRC 
Consumer Response Center 
CRF 
Case report form 
CRO 
Contract research organization 
ECG 
Electrocardiogram 
°F 
Degrees Fahrenheit 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbsAg 
Hepatitis B surface antigen 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
ITT 
Intent to treat 
IVRS 
Interactive voice response system 
kg 
Kilogram(s) 
m 
Meter(s) 
mg  
Milligram(s)  
mL 
Milliliter(s)  
NE 
nicotine equivalent 
ng 
Nanogram(s) 
NNAL 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
PAVE 
Pilot Ambulatory VBM-FG2 exposure 
PK 
pharmacokinetic(s) 
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Protocol No: COV-VER-01-13 
 
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PP 
Per protocol 
RBC 
Red blood count 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
S-PMA 
S-phenylmercapturic acid 
TBD 
To be determined 
US 
United States 
WBC 
White blood cell 
 
 
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Protocol No: COV-VER-01-13 
 
Issue Date Amendment 1: 20 August 2013 
 
 
15 REFERENCES  
1. Hatsukami DK, Joseph AM, Lesage M, et al. Developing the Science Base for 
Reducing Tobacco Harm. Nicotine Tob Res. 2007; Suppl 4:S537-553. 
2. ICH Guideline for Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting (E2A). Federal Register. Vol. 60, March 1, 1995, p. 11284. 
3. ICH Guideline for Good Clinical Practice: Consolidated Guidance (E6). Federal 
Register. Vol. 62, May 9, 1997, p. 25692. 
4. Nebeker JR, Barach P, Samore MH. Clarifying Adverse Drug Events: A Clinician’s 
Guide to Terminology, Documentation, and Reporting. Ann Intern Med. 
2004;140:795-801. 
5. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and 
management. Lancet 2000;356:1255-1259. 
6. U.S. Department of Health and Human Services. HIPAA Privacy Rule. Information 
for Researchers. De-identifying Protected Health Information Under the Privacy 
Rule. Available online at http://privacyruleandresearch.nih.gov/pr_08.asp#8a. Last 
accessed August 30, 2011.  
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Appendix 1  Investigator Obligations 
Each clinical investigator is responsible for conducting the study in accordance with the 
protocol, all applicable laws, regulations, and the ICH Consolidated Guideline:  GCP. 
A. Institutional Review Board (IRB) Review/Approval 
It is the Investigator’s responsibility to ensure that all aspects of the ethics review are 
conducted in accordance with the current Declaration of Helsinki as described in the ICH 
GCP guidelines, and/or in accordance with local laws, whichever provides the greatest 
level of protection for the study subjects.  The protocol and any information supplied to 
the subject to obtain informed consent, including written informed consent forms (ICF), 
subject recruitment procedures (e.g., advertisements) and written information (e.g., 
information leaflets), must be reviewed and approved by a qualified IRB prior to 
enrolling subjects in the study.  Prior to study initiation, ALCS must receive 
documentation of the IRB approval, which specifically identifies the study/protocol and a 
list of the committee members. 
Amendments to the protocol and revisions to the ICF must also be submitted to and, if 
required, approved by the IRB. 
At intervals required by the IRB, but not less than annually, the Investigator must submit 
to the IRB a progress report with a request for re-evaluation and re-approval of the study.  
A copy of the progress report and re-approval of the study must be sent to ALCS. 
When ALCS provides the Investigator with an Expedited Safety Report, the Investigator 
must promptly forward a copy to the IRB according to local regulatory requirements or 
institution procedures. 
After completion or termination of the study, Investigators should follow any applicable 
institutional policies and procedures for notifying the IRB of the study's completion.  
This submission and approval or acknowledgement should be sent to ALCS for 
submission in the trial master file.   
As part of the record retention requirements for the study, the Investigator must maintain 
documentation of all submission, correspondence, and approvals to and from the IRB. 
B. Informed Consent 
Informed consent must be obtained from each subject prior to entering the study, and 
must meet the requirements of the Declaration of Helsinki as defined by the ICH GCP 
guidelines and/or conform to local laws, whichever provides the greatest level of 
protection.  Each subject must be provided, in an understandable manner, written and 
verbal information that describes the nature and duration of the study.  Additionally, the 
subject must be allowed adequate time to consider the potential risks and benefits 
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associated with his/her participation in the study.  The informed consent must also 
contain language that allows ALCS (or designated representative), regulatory authorities, 
and the IRB direct access to the subject’s source documents for the purpose of review and 
copying. 
The consent form must be signed and dated by the study subject.  In situations where 
study subjects are not legally competent to provide consent (e.g., a minor or mentally 
incapacitated subject) written consent must be obtained from an authorized guardian or 
representation.  The ICF must also be signed and dated by the individual obtaining the 
informed consent. 
The Investigator, as part of the study documentation, must retain the signed and dated 
ICF and must provide a copy to each subject or authorized representative. 
C. Data Reporting and Case Report Forms (CRFs) 
Data reflecting the subject’s participation in the study and experiences with the test 
product must be reported by the Investigator to ALCS.  These data must be recorded on 
CRFs or other media approved by ALCS.  For rules regarding completion and correction 
of CRFs, see the CRF instructions that accompany the CRFs.  Case report forms must be 
signed and dated by the Investigator and must be submitted in a timely manner to ALCS. 
D. Record Retention 
The Investigator must ensure that all records pertaining to the conduct of the clinical 
study, including signed CRFs, ICFs, test product accountability records, source 
documents, and other study documentation are adequately stored for the required time 
period to allow for retrieve and reconstruction of the study.  This documentation must be 
retained for the most conservative time period below: 
• 2 years following approval/authorization of the last marketing application that the 
data was used to support; or 
• 5 years after formal discontinuation of the clinical development program; or 
• a record retention period mandated by any national and/or local laws, regulations, 
and customs;  
• or as specified by ALCS. 
The Investigator must not destroy any records associated with the study without receiving 
approval from ALCS.  The Investigator must notify ALCS in the event of accidental loss 
or destruction of any study records.  If the Investigator leaves the institution where the 
study was conducted, ALCS must be contacted to arrange alternative record storage 
options. 
Study documentation includes all CRFs; Safety reports received from ALCS; Serious 
Adverse Experience Reports sent to ALCS; data correction forms; source documents; 
monitoring logs; sponsor-investigator correspondence; protocols and amendments; 
clinical supplies receipts; dispensing and final disposition records; IRB correspondence 
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and approvals; signed consent forms; and Statement of Investigator forms/Investigator 
Agreements. 
Source documents include all original records or observation, results, and activities 
necessary to reconstruct and evaluate the study.  Source documents include, but are not 
limited to, laboratory reports, electrocardiogram tracings, X-ray films, ultrasound 
photographs, subject diaries, subject progress notes, hospital charts, appointment books, 
radiology reports or pharmacy records, and any other records or reports of procedures 
performed during the study.  Source documents also may include copies of the CRF or 
sponsor supplied worksheets when original information is recorded directly onto these 
forms. 
Whenever possible, an original recording of an observation must be retained as the source 
document.  However, a photocopy of a record is acceptable provided it is legible and is a 
verified copy of the original document. 
E. Deviation from the protocol 
The Investigator must not deviate from the protocol without prior written approval from 
ALCS and as required, the IRB.  In medical emergencies, the Investigator should use 
medical judgment and remove the subject from immediate hazard.  Altria Client Services 
and the IRB must be notified regarding the type of emergency and course of action taken. 
F. Investigational Product Accountability 
The Investigator must maintain adequate and accurate records (including quantities and 
dates) for clinical supplies received from ALCS, dispensed during the study, and unused 
clinical supplies that were returned or destroyed.  All clinical supplies must be accounted 
for at the termination of the study and a written explanation must be provided for 
discrepancies.  All unused clinical supplies must be returned promptly to ALCS or, if 
authorized in writing by ALCS, properly destroyed at the study site (except for retained 
samples in the case of bioavailability/bioequivalence studies). 
G. Study Monitoring 
Each study will be monitored by qualified representatives of ALCS according to a 
predetermined monitoring plan.  Monitoring visits provide ALCS with the opportunity to: 
evaluate the progress of the study; verify the accuracy and completeness of CRFs; assure 
that all protocol requirements, applicable laws and/or regulations and investigator 
obligations are being fulfilled; and resolve any inconsistencies in the study records.  The 
Investigator must allow ALCS’s representatives to periodically review, at mutually 
convenient times during the study and after the study has been completed, all CRFs and 
office, hospital, laboratory records supporting the participation of each subject in the 
study.  Case report forms and supporting documentation of the study conduct must be 
kept up-to-date and available for each monitoring visit. 
H. Sponsor Audits 
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At some point during the study, individuals from ALCS’s Quality Assurance group or 
their authorized representative may visit the Investigator’s site to conduct an audit of the 
study.  The purpose of this visit will be to determine the Investigator’s adherence to the 
protocol, applicable regulations, and ALCS’s procedures, in addition to assessing the 
accuracy of the study data.  Prior to initiating this audit, the Investigator will be contacted 
by ALCS to arrange a convenient time for this visit.  The Investigator and staff are 
expected to cooperate with the auditors and allow access to all subject records supporting 
the CRFs and other study-related documents. 
I. Inspection by Regulatory Authorities 
At some point during or after the study, a regulatory authority may visit the Investigator 
to inspect the study.  The Investigator and staff are expected to cooperate with the 
inspectors and allow access to all source documents supporting the CRFs and other 
study-related documents.  The Investigator must immediately notify ALCS when 
contacted by any regulatory authority for purposes of conducting an inspection and allow 
ALCS to be present at the inspection. 
J. Financial Disclosure by Clinical Investigators 
All clinical investigators participating in clinical studies subject to FDA Regulation 
21 CFR Part 54 – Financial Disclosure by Clinical Investigators are required prior to 
study initiation to submit a completed Financial Disclosure Form that sufficiently details 
any financial interests and arrangements that apply.  For the purpose of this regulation, 
clinical investigator is defined as any investigator or subinvestigator who is directly 
involved in the treatment or evaluation of research subjects, including the spouse and any 
dependent child of each investigator or subinvestigator.  These requirements apply to 
both US and foreign clinical investigators conducting covered clinical studies.   
Any new investigators or subinvestigators added to the covered clinical study during its 
conduct must also submit a completed Financial Disclosure Form.  The clinical 
investigators will also be reminded that they must report any changes in their financial 
information regarding significant equity interests and significant payments during the 
course of the study and for a period of 1 year after completion of their participation in the 
covered clinical study. 
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Protocol No: COV-VER-01-13 
 
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Appendix 2: Subject Screener / Tobacco History 
Cigarettes: 
 
1. Do you now smoke cigarettes every day, some days, or not at all?  
Every day 
Some days 
Not at all (Skip to Question 8) 
 
2. How many months or years have you smoked cigarettes fairly regularly (i.e. on a 
routine basis) since turning 21 years of age (i.e. after your 21st birthday)? 
______ Months (only include months since turning 21)  
______ Years (only include years since turning 21) 
 
3. Have you been smoking fairly regularly (i.e. on a routine basis) for more than 
6 months? 
Yes  
No 
 
4. On average, about how many cigarettes do you now smoke each day? 
_________________cigarettes per day  
 
5. During the past 6 months, how many times have you stopped smoking cigarettes for 
24 hours or longer because you were trying to quit? 
_________ Number of times 
 
6. Are you planning to quit smoking cigarettes in the next 30 days? 
Yes 
No 
 
7. Are you interested in tobacco product alternatives to cigarettes? 
 
Yes  
 
 
No 
 
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Protocol No: COV-VER-01-13 
 
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8.There are many different types of tobacco products.  Please read the description on the left, and 
then indicate with check marks the tobacco products that (1) you have ever used, even 
once, and (2) now use every day, some days or not at all. 
Tobacco Product 
 
Check the box 
next to each 
tobacco product 
that you have 
EVER used, 
even once: 
Of the tobacco products 
that you have ever used, 
check whether you NOW 
use the product 
Every 
day 
Some 
days 
Not at 
all 
Bidis or kreteks:  Popular in other parts of the 
world.  Bidis are small hand-rolled cigarettes.  
Kreteks are clove-flavored cigarettes.  
 
 
 
 
Electronic cigarettes:  Often look like regular 
cigarettes but run on a battery.  E-cigarette 
brands include NJOY, Blu, GreenSmoke and 
21st Century. 
 
 
 
 
Premium cigars:  Come in different sizes and 
shapes. 
Some examples of premium cigar brands are 
Macanudo, Arturo Fuente and Romeo y Julieta. 
 
 
 
 
Cigarillos:  Generally narrower and shorter 
than premium cigars; they may come with 
plastic or wooden tips.  Examples of cigarillo 
brands are Black & Mild, Swisher Sweets, and 
Dutch Masters. 
 
 
 
 
Large cigars:  Not premium cigars; generally 
wider and longer than cigarillos.  Phillies Blunt 
cigars is an example of a large cigar brand. 
 
 
 
 
Little cigars:  Look similar to cigarettes, 
except they are brown and have a filter like a 
cigarette.  Some examples of little filtered cigar 
brands are Winchester, Captain Black and 
Wrangler. 
 
 
 
 
Chewing tobacco:  Coarsely shredded and 
sold in pocket-sized packs of loose tobacco 
leaves or in a “plug” or “twist” form.  Brands 
include Red Man, Levi Garrett and Beech-nut. 
 
 
 
 
Snuff (dip):  Finely ground form of tobacco 
that is usually sold in a tin.  Brands include 
Grizzly, Copenhagen and Skoal. 
 
 
 
 
Snus:  Spitless tobacco product that comes in 
small pouches and is usually sold in a tin.  
Camel Snus is an example of a snus brand. 
 
 
 
 
Dissolvable tobacco products:  Designed to 
dissolve in the mouth.  Examples include 
Camel Orbs, Strips, and Sticks.  Others include 
Ariva and Stonewall. 
 
 
 
 
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Protocol No: COV-VER-01-13 
 
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Hookah:  Or “narghile” pipe, is a type of water 
pipe used to smoke tobacco. 
 
 
 
 
Pipe. A regular smoking pipe has a bowl for 
tobacco, stem and mouthpiece 
 
 
 
 
 
9. Please indicate with check marks the nicotine replacement product or products that (1) 
you have ever used, even once, and (2) now use every day, some days or not at all. 
Nicotine Replacement Product 
 
 
Check the box 
next to each 
nicotine 
replacement 
product that 
you have EVER 
used, even once: 
Of the nicotine 
replacement products 
that you have ever used, 
check whether you NOW 
use the product 
Every 
day 
Some 
days 
Not 
at all 
Patch 
 
 
 
 
Gum 
 
 
 
 
Lozenge 
 
 
 
 
Nasal spray 
 
 
 
 
Inhaler 
 
 
 
 
 
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Protocol No: COV-VER-01-13 
 
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Appendix 3: Potential Purchase Interest Questionnaire 
 
1. 
Now that you have tried it, how likely would you be to buy VBM-FG2 if it was 
available in stores where you shop and priced at about $1.00 less than the price of 
premium cigarette brands for a package of 16 VBM-FG2 discs? Would you say 
that you… 
 
A. Definitely would buy 
B. Probably would buy 
C. Might or might not buy 
D. Probably would not buy 
E. Definitely would not buy 
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Protocol No: COV-VER-01-13 
 
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Appendix 4: Fagerström Test for Cigarette Dependence1  
 
1. 
How soon after you wake up do you smoke your first cigarette? 
 Within 5 minutes  
 6 – 30 minutes   
 31 – 60 minutes 
 After 60 minutes 
 
2. 
Do you find it difficult to refrain from smoking in places where it is forbidden 
(e.g., in church, at the library, in movies, etc.)? 
 Yes   
 No   
 
3. 
Which cigarette would you hate most to give up?  
 The first one in the morning  
 All others  
 
 
4. 
How many cigarettes per day do you smoke? 
 10 or less  
 11 to 20   
 21 to 30 
 31 or more 
 
 
5. 
Do you smoke more frequently during the first hours after waking than  
during the rest of the day? 
 Yes  
 No  
 
 
6. 
Do you smoke if you are so ill that you are in bed most of the day? 
 Yes  
 No  
 
 
1Fagerstrom, Determinants of tobacco use and renaming the FTND to the Fagerstrom Test for 
Cigarette Dependence, Nicotine Tob Res. 2012 Jan;14(1):75-8. doi: 10.1093/ntr/ntr137. Epub 
2011 Oct 24. 
 
 
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Protocol No: COV-VER-01-13 
 
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Appendix 5: Past 7 Day Cigarettes Use Questionnaire 
 
Cigarettes: 
 
1. Do you now smoke cigarettes every day, some days, or not at all? 
Every day  
Some days  
Not at all (skip final 2 questions) 
 
2. Now think about the past 7 days up to and including today.  On how many of 
the past 7 days did you smoke cigarettes? 
_________________Days  
 
3. On average, on those days, how many cigarettes did you usually smoke each 
day? 
_________________Cigarettes 
 
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Protocol No: COV-VER-01-13 
 
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Appendix 6: Other Tobacco or Nicotine Containing Product Use 
Questionnaire  
 
Cigars, Cigarillos and/or Little Cigars: 
 
1. Now think about the past 7 days up to and including today.  During the past 
7 days, did you smoke any type of cigars, cigarillos and/or little cigar every day, 
some days, or not at all? 
Every day (Skip to question 3) 
Some days  
Not at all (Skip to question 4) 
 
2. On how many of the past 7 days did you smoke cigars, cigarillos, and/or little 
cigars? 
_________________Days  
 
3. On average, on those days, how many cigars, cigarillos, and/or little cigars did 
you usually smoke each day? 
_________________cigars, cigarillos, and/or little cigars per day 
 
Electronic Cigarettes (Often look like regular cigarettes but run on a battery.): 
  
4. Now think about the past 7 days up to and including today.  During the past 
7 days, did you smoke and/or vape electronic cigarettes every day, some days, 
or not at all? 
Every day (Skip to question 6) 
Some days  
Not at all (Skip to question 7) 
 
5. On how many of the past 7 days did you smoke and/or vape electronic 
cigarettes? 
_________________Days  
 
6. On average, on those days, how many electronic cigarettes cartomizers, refills, 
and/or disposables did you usually smoke and/or vape each day? 
_________________cartomizers, refills, and/or disposables per day 
 
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Chewing Tobacco, Snuff, and/or Dip: 
 
7. Now think about the past 7 days up to and including today.  During the past 
7 days, did you use any type of chewing tobacco, snuff and/or dip every day, 
some days, or not at all? 
Every day (Skip to question 9) 
Some days  
Not at all (Skip to question 10) 
 
8. On how many of the past 7 days did you use chewing tobacco, snuff and/or dip? 
_________________Days  
 
9. On average, on those days, how many times did you usually use chewing 
tobacco, snuff, and/or dip each day? 
_________________chewing tobacco, snuff, and/or dip per day 
 
Snus (Spitless tobacco product that comes in small pouches and is usually sold in a 
tin.): 
 
10. Now think about the past 7 days up to and including today.  During the past 
7 days, did you use snus every day, some days, or not at all? 
Every day (Skip to question 12) 
Some days  
Not at all (Skip to question 13) 
 
11. On how many of the past 7 days did you use snus? 
_________________Days  
 
12. On average, on those days, how many times did you usually use snus each day? 
_________________snus per day 
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Protocol No: COV-VER-01-13 
 
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Other Tobacco or Nicotine Containing Products: (hookah, pipe, 
orbs, sticks, strips, nicotine patch, nicotine gum, nicotine lozenge, etc) 
 
**Do not include VBM-FG2 tobacco product disc information** 
 
13. Now think about the past 7 days up to and including today.  During the past 
7 days, did you use at least one type of any other tobacco or nicotine containing 
product every day, some days, or not at all? 
Every day (Skip to question 15) 
Some days  
Not at all (Skip final 2 questions) 
 
14. On how many of the past 7 days did you use any other tobacco or nicotine 
containing product? 
_________________Days  
 
15. On average, on those days, how many times did you usually use at least one 
type of any other tobacco or nicotine containing product each day? 
_________________Other tobacco or nicotine containing products 
 
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Protocol No: COV-VER-01-13 
 
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Appendix 7: Quit Attempts and Quitting Intentions Questionnaire – 
Day 1 
 
1. During the past 30 days have you stopped smoking cigarettes for 24 hours or 
longer because you were trying to quit? 
 
 
Yes  
 
 
No (if no, skip to question 3) 
 
2. How many times during the past 30 days have you stopped smoking cigarettes 
for 24 hours or longer because you were trying to quit? 
 
 
____Number of Times 
 
3.  Are you planning to quit smoking in the next 30 days? 
 
Yes  
 
 
No  
 
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Protocol No: COV-VER-01-13 
 
Issue Date Amendment 1: 20 August 2013 
 
Appendix 8: Quit Attempts and Quitting Intentions Questionnaire - 
End of Study 
 
1. During the past 30 days have you stopped smoking cigarettes for 24 hours or 
longer because you were trying to quit? 
 
 
Yes 
 
 
No (if no, skip to question 3) 
 
2. How many times during the past 30 days have you stopped smoking cigarettes 
for 24 hours or longer because you were trying to quit? 
 
 
____Number of Times 
 
3. Do you now smoke cigarettes every day, some days, or not at all? 
Every day 
Some days  
Not at all (Skip final question) 
 
4.  Are you planning to quit smoking in the next 30 days? 
 
Yes  
 
 
No  
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Protocol No: COV-VER-01-13 
 
Issue Date Amendment 1: 20 August 2013 
 
 
Appendix 9: Protocol Amendments 
Amendment 1 (20 August 2013) 
The following changes were introduced to the Final Protocol (09 August 2013) via 
Protocol Amendment 1 (20 August 2013). 
Section 4.1 Inclusion 
From: 
3) 
consumed a minimum of 10 manufactured CPD daily during the last 12 months. 
To: 
3) 
consumed a minimum of 10 manufactured CPD daily during the last 126 months 
(entire 6 month period must have occurred after subject turned 21 years of age). 
Section 6.3.18.1 Urine sample Collection for Biomarker Analysis 
From: 
All aliquots will be prepared and then stored at -20ºC or lower until analyzed or shipped.  
The additional back-up sample may be used for potential re-assays of BOEs and will be 
stored until the Clinical Study Report is finalized. 
Table A:  Samples for Analysis of Urinary Biomarkers of Exposure 
Urine Biomarkers 
Number of 
Aliquots 
Aliquot 
volume (mL) 
Total Volume for 
Parameter (mL) 
Container 
Type 
Total NNAL 
2 
10 
20 
HDPE 
Nicotine Equivalents 
2 
5 
10 
HDPE 
S-PMA 
2 
5 
10 
HDPE 
Creatinine 
2 
5 
10 
HDPE 
Additional Back-up Sample  
1 
50 
50 
HDPE 
Banked Sample 
1 
50 
50 
HDPE 
 
To: 
All aliquots will be prepared and then stored at -20-70ºC or lower until analyzed or 
shipped.  The additional back-up sample may be used for potential re-assays of BOEs 
and will be stored until the Clinical Study Report is finalized. 
HIGHLY CONFIDENTIAL – PROPRIETARY INFORMATION 
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Protocol No: COV-VER-01-13 
 
Issue Date Amendment 1: 20 August 2013 
 
Table A:  Samples for Analysis of Urinary Biomarkers of Exposure 
Urine Biomarkers 
Number of 
Aliquots 
Aliquot 
volume (mL) 
Total Volume for 
Parameter (mL) 
Container 
Type 
Total NNAL 
2 
10 
20 
HDPE TBD 
Nicotine Equivalents 
2 
5 
10 
HDPE TBD 
S-PMA 
2 
5 
10 
HDPE TBD 
Creatinine 
2 
5 
10 
HDPE TBD 
Additional Back-up Sample  
1 
50 
50 
HDPE TBD 
Banked Sample 
1 
50 
50 
HDPE TBD 
 
Section 6.3.18.2 
Blood Sample Collection for Biomarker Analysis 
From: 
A 4-mL blood sample for COHb analysis will be drawn in sodium heparin (green top) 
vacutainer tubes.  Immediately following collection, the blood samples will be gently 
inverted and refrigerated.  The whole blood samples will be properly labeled and 
delivered to the laboratory. An additional 2 (5 mL) samples of blood (1 for serum and 
1 for EDTA/plasma) will be collected at Visit 3 and again at End of Study for sample 
banking.  Details on blood sample volumes for BOE analysis, clinical laboratory 
evaluations, and serology are noted in Table B. 
Table B:  Blood Sample Volumes 
Parameter 
Maximum Blood 
Volume Per Sample 
(mL) 
Approximate 
Number of Blood 
Samples 
Approximate Total 
Blood Volume 
Hematology 
4 
2 
8 
Chemistry 
8.5 
2 
17 
HIV, HBsAg, anti-HCV 
8.5 
1 
8.5 
COHb 
4 
6 
24 
Sample Banking – Serum 
5 
2 
10 
Sample Banking – Plasma 
5 
2 
10 
Serum Pregnancy 
8.5 
6 
51 
Total 
Male 
77.5 
Female 
128.5 
 
To: 
A 4-mL blood sample for COHb analysis will be drawn in sodium heparin (green top) 
vacutainer tubes.  Immediately following collection, the blood samples will be gently 
inverted and refrigerated.  The whole blood samples will be properly labeled and 
delivered to the laboratory. An additional 2  (5 mL) samples of blood (1 for serum 
[5 mL] and 1 for EDTA/plasma [4 mL]) will be collected at Visit 3 and again at End of 
Study for sample banking.  Details on blood sample volumes for BOE analysis, clinical 
laboratory evaluations, and serology are noted in Table B. 
HIGHLY CONFIDENTIAL – PROPRIETARY INFORMATION 
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Protocol No: COV-VER-01-13 
 
Issue Date Amendment 1: 20 August 2013 
 
Table B:  Blood Sample Volumes 
Parameter 
Maximum Blood 
Volume Per Sample 
(mL) 
Approximate 
Number of Blood 
Samples 
Approximate Total 
Blood Volume 
Hematology 
4 
2 
8 
Chemistry 
8.5 
2 
17 
HIV, HBsAg, anti-HCV 
8.5 
1 
8.5 
COHb 
4 
6 
24 
Sample Banking – Serum 
5 
2 
10 
Sample Banking – Plasma 
5 4 
2 
10 8 
Serum Pregnancy 
8.5 
6 
51 
Total 
Male 
775.5 
Female 
1286.5 
 
Section 7.3 
Storage, Handling and Dispensing 
From: 
Subjects in the Test Group will initially receive 7 tubes of VBM-FG2 at Visit 3.  Subjects 
will be asked to bring back all product packages (empty, partially used, unopened) and 
unused product at each subsequent study visit.  Study sites will perform accountability on 
the returned product and tailor future dispensation numbers based on product use.  If a 
subject has used more than 6 of the 7 tubes received, an additional 3 tubes will be 
dispensed for the next week.  At subsequent visits, additional tubes will be dispensed in 
the same manner (for example; if 9 of the 10 tubes are used, 13 tubes will be given.  This 
will continue to a maximum of 16 tubes in 1 week; otherwise subjects will receive the 
same amount (7 unopened tubes per week).  Unused tubes will be re-dispensed to the 
same subject. 
To: 
Subjects in the Test Group will initially receive 7 tubes of VBM-FG2 at Visit 3.  Subjects 
will be asked to bring back all product packages (empty, partially used, unopened) and 
unused product at each subsequent study visit.  Study sites will perform accountability on 
the returned product and tailor future dispensation numbers based on product use.  If a 
subject has used more than 6 of the 7 tubes received, an additional 3 tubes will be 
dispensed for the next week (up to a maximum of 12 tubes in 1 week).  At subsequent 
visits, additional tubes will be dispensed in the same manner (for example; if 9 of the 
10 tubes are used, 1312 tubes will be given).  This will continue to a maximum of 16 
tubes in 1 week; oOtherwise subjects will receive the same amount (7 unopened tubes per 
week).   Subjects will be instructed that they should not use more than 24 discs per 
day.  Unused tubes will be re-dispensed to the same subject. 
Appendix 2: Subject Screener / Tobacco History 
From: 
1. Do you now smoke cigarettes every day, some days, or not at all?  
Every day 
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Protocol No: COV-VER-01-13 
 
Issue Date Amendment 1: 20 August 2013 
 
Some days 
Not at all (Skip to Question 7) 
 
2. Have you been smoking fairly regularly (i.e. on a routine basis) for more than 1 year? 
Yes ________ number of years 
No 
 
3. On average, about how many cigarettes do you now smoke each day? 
_________________cigarettes per day  
 
4. During the past 12 months, how many times have you stopped smoking cigarettes for 
24 hours or longer because you were trying to quit? 
_________ Number of times 
To: 
1. Do you now smoke cigarettes every day, some days, or not at all?  
Every day 
Some days 
Not at all (Skip to Question 78) 
 
2. How many months or years have you smoked cigarettes fairly regularly (i.e. on a 
routine basis) since turning 21 years of age (i.e. after your 21st birthday)? 
______ Months (only include months since turning 21)  
______ Years (only include years since turning 21) 
 
2 3. Have you been smoking fairly regularly (i.e. on a routine basis) for more than 1 year 
6 months? 
Yes ________ number of years 
No 
 
 
 
3 4. On average, about how many cigarettes do you now smoke each day? 
_________________cigarettes per day  
 
4 5. During the past 12 6 months, how many times have you stopped smoking cigarettes 
for 24 hours or longer because you were trying to quit? 
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