Effect of Oral Black Raspberry Administration on Oral Cell DNA Adducts in Smokers
Phase: NA
Conditions: Oral Cancer, Smoking, DNA Damage, Oxidative Stress
Sponsor: Milton S. Hershey Medical Center

Page 1 of 31 (V.01/21/2019) 
                                                                                       
HRP-592 - Protocol for Human Subject 
Research with Use of Test Article(s)
Protocol Title:
Effect of oral black raspberry administration on oral cell DNA adducts in smokers
Principal Investigator:
Name: Karam El-Bayoumy 
Department: Biochemistry and Molecular Biology
Telephone:  x1005
E-mail Address: kelbayoumy@pennstatehealth.psu.edu
Version Date:
5-15-24
Clinicaltrials.gov Registration #:
 NCT04372914
Important Instructions for Using This Protocol Template:
This template is provided to help investigators prepare a protocol that includes the necessary information needed by the 
IRB to determine whether a study meets all applicable criteria for approval.
1.
GENERAL INSTRUCTIONS:  

Prior to completing this protocol, ensure that you are using the most recent version by verifying the 
protocol template version date in the footer of this document with the current version provided in the 
CATS IRB Library.

Do not change the protocol template version date located in the footer of this document.

Some of the items may not be applicable to all types of research.  If an item is not applicable, please 
indicate as such or skip question(s) if indicated in any of the instructional text. 

GRAY INSTRUCTIONAL BOXES: 
o
Type your protocol responses below the gray instructional boxes of guidance language.  If the 
section or item is not applicable, indicate not applicable.
o
Penn State College of Medicine/Penn State Health researchers: Delete the instructional boxes 
from the final version of the protocol prior to upload to CATS IRB (http://irb.psu.edu).  
o
Penn State researchers at all other campuses: Do NOT delete the instructional boxes from the 
final version of the protocol.

Add the completed protocol template to your study in CATS IRB (http://irb.psu.edu) on the “Basic 
Information” page.  
2.
CATS IRB LIBRARY: 

Documents referenced in this protocol template (e.g. SOP’s, Worksheets, Checklists, and Templates) can be 
accessed by clicking the Library link in CATS IRB (http://irb.psu.edu).
3.
PROTOCOL REVISIONS: 

When making revisions to this protocol as requested by the IRB, please follow the instructions outlined in 
the Study Submission Guide available in the Help Center in CATS IRB (http://irb.psu.edu) for using track 
changes. 
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
Update the Version Date on page 1 each time revisions are made.
If you need help…
University Park and other campuses:
Office for Research Protections Human Research 
Protection Program
The 330 Building, Suite 205
University Park, PA 16802-7014
Phone: 814-865-1775
Fax: 814-863-8699
Email: irb-orp@psu.edu
College of Medicine and Penn State Health:
Human Subjects Protection Office
90 Hope Drive, Mail Code A115, P.O. Box 855
Hershey, PA 17033
(Physical Office Location: Academic Support Building 
Room 1140)
Phone: 717-531-5687
Email: irb-hspo@psu.edu  
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Table of Contents
1.0
Objectives
2.0
Background
3.0
Inclusion and Exclusion Criteria
4.0
Recruitment Methods
5.0
Consent Process and Documentation
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
7.0
Study Design and Procedures
8.0
Subject Numbers and Statistical Plan
9.0
Data and Safety Monitoring Plan
10.0
Risks
11.0
Potential Benefits to Subjects and Others
12.0
Sharing Results with Subjects
13.0
Subject Payment and/or Travel Reimbursements
14.0
Economic Burden to Subjects
15.0
Resources Available
16.0
Other Approvals
17.0
Multi-Site Study
18.0
Adverse Event Reporting
19.0
Study Monitoring, Auditing and Inspecting
20.0
Future Undetermined Research: Data and Specimen Banking
21.0
References
22.0
Confidentiality, Privacy and Data Management
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1.0
Objectives
1.1
Study Objectives
In this Black Raspberry Oral Cancer Prevention (BROCAP) study we will determine for the first time the 
effects of local black raspberry (BRB) delivery on formation of 1) covalent carcinogen-derived DNA 
adducts and 2) oxidative DNA damage (8-OXO-dG) in exfoliated oral keratinocytes and 3) systemic 
oxidative DNA damage (8-OXO-dG) in urine in current smokers.  Based on preclinical data, we 
hypothesize that daily black raspberry administration will reduce the levels of DNA damage due to 
tobacco smoke exposure.  
1.2
Primary Study Endpoints
Exfoliated buccal mucosal cell levels of the tobacco specific nitrosamine (N’-nitrosonornicotine , NNN)-
derived DNA adduct 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)-releasing adduct.  
1.3
Secondary Study Endpoints
Exfoliated buccal mucosal cell levels of the benzo[a]pyrene (B[a]P)-derived DNA adduct. 
Exfoliated buccal mucosal cell levels of the oxidative DNA damage biomarker 8-OXO-dG.
Systemic oxidative DNA damage urinary biomarker 8-OXO-dG.
Tobacco smoke exposure urinary biomarker cotinine.
Systemic lipid peroxidation biomarker urinary 8-isoprostane (8-IsoP).
Urinary anthocyanin.
2.0
Background 
2.1
Scientific Background and Gaps
Treating oral squamous cell carcinoma (OSCC) at late stages, even with recent advances in targeting 
therapies, continues to be a major challenge [1], and thus prevention should be the most effective 
strategy to manage and control this disease.  Our prevention approach focuses on elucidating the 
molecular mechanisms responsible for the induction of OSCC by environmental carcinogens, followed by 
development of targeted intervention/chemoprevention strategies.  Tobacco use remains a high OSCC 
risk factor resulting from exposure to potent tobacco carcinogens including polycyclic aromatic 
hydrocarbons (PAHs) such as dibenzo[a,l]pyrene (DB[a,l]P), benzo[a]pyrene (B[a]P) and tobacco-specific 
nitrosamines (TSNA) such as N’-nitrosonornicotine (NNN). To assess effects of these carcinogens on oral 
mucosa, we developed a novel OSCC mouse model using DB[a,l]P and its fjord region diol epoxide 
(DB[a,l]PDE) [2, 3]. Our preliminary results and literature data demonstrated the presence of covalent 
B[a]P and NNN derived adducts and 8-OXO-dG in buccal cells of smokers [4-6].  Importantly, we showed 
that dietary intervention with freeze-dried black raspberries (BRB) powder inhibited carcinogen-induced 
DNA damage, mutagenesis and carcinogenesis in the mouse oral cavity [3, 7]. Clinical trial data 
demonstrated topical application of a BRB mucoadhesive gel significantly reduced loss of heterozygosity 
(LOH) events at putative tumor suppressor gene loci [8]. These LOH data, which show BRB-enabled 
removal of cells with allelic imbalances or reduced additional LOH events, further support BRB inhibitory 
role of DNA damage [3, 7].  Altogether, these data suggest that BRB may be effective in reducing the 
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levels of DNA damage in the oral cavity resulting from tobacco smoke exposure in smokers.  However, 
there have been no clinical studies of the effects of BRB administration in this regard.
2.2
Previous Data
Based on our published preclinical findings [7, 9, 10] and preliminary data, we hypothesize that BRB 
administration will reduce the levels of DNA damage (B[a]P & NNN-derived adducts & 8-OXO-dG) in 
buccal keratinocytes from healthy smokers.  Previous clinical trials by members of our team and others 
have identified the efficacy of BRB at reducing the histologic grade, loss of heterozygosity events and 
clinical size of pre-malignant oral intraepithelial neoplasia (OIN) [8].  BRB also suppressed the expression 
of antiapoptotic and proinflammatory genes in tumor and at-risk mucosal tissues from oral squamous 
cell carcinoma patients [11] supporting a preventive/therapeutic role for BRB. Based on these results, 
we will conduct a phase 0 clinical trial to examine, for the first time, the efficacy of BRB at reducing 
smoking related DNA damage in healthy smokers.  The previous BRB OIN clinical studies precluded 
tobacco use.  As tobacco use remains a key OSCC risk factor, our study is essential to assess the 
protective efficacy of BRB on DNA damage induced by tobacco carcinogens in current smokers.  
Additionally, Mallery et al [12] demonstrated that human oral epithelium contains the requisite 
hydrolytic, phase II and efflux transporting enzymes necessary for local enteric recycling and sustained 
exposure to active BRB metabolites.  We have had extensive experience with conducting similar 
nutrient-based intervention trials in healthy adult smokers and non-smokers with several of the same 
measured outcomes (e.g. biomarkers of oxidative stress) including interventions with selenium [13, 14], 
glutathione [15], liposomal glutathione [16], and omega-3 fatty acids [17, 18].  In most cases these 
previous trials were similarly designed in regard to number and frequency of visits or were even longer 
in duration and were highlighted by high levels of subject compliance.  
2.3
Study Rationale
On the basis of our published results, preliminary data, and results reported in the literature, there is a 
strong premise underlying this research.  This includes data suggesting that BRB can impact specific DNA 
repair mechanisms in oral cells [9, 10].  Major carcinogenic agents in tobacco smoke include polycyclic 
aromatic hydrocarbons such as benzo[a]pyrene (B[a]P) and tobacco specific nitrosamines such as N-
nitrosonornicotine (NNN), as well as a variety of powerful oxidants including reactive free radicals.  
These agents can induce cancer development through formation of DNA adducts including B[a]P 
adducts, pyridyloxobutyl adducts from NNN, also known as “HPB-releasing adducts” since their 
measurement is based on the release of 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB), , and 8-oxo-2'-
deoxyguanosine (8-OXO-dG) from free radicals.
Our previous studies confirmed that human surface epithelium and human OSCC keratinocytes 
possess the Phase 1 enzymes necessary for PAH activation [19] and BRB constituents can alter Phase I 
and II in a manner consistent with cancer prevention [3].  Furthermore, based on the abundant phenolic 
constituents in BRB (e.g. anthocyanins), it is logical to propose that BRB helps preserve the cellular redox 
poise, enhance redox scavenging and therefore function to prevent oxidative damage.  In fact, this 
proposition is in line with our findings demonstrating that BRB inhibits oxidative stress in human oral 
cells [9].  In addition to a facilitating cytoprotection, cellular reducing equivalents are involved in many 
biosynthetic reactions including deoxyribonucleotides (dNTPs) that are essential components for DNA 
repair [20].  Furthermore, BRB contains appreciable levels of minerals such as Mg+2 that are key 
cofactors necessary for optimal DNA BER enzyme function [21-23].  In addition, our previous study 
showed that human oral mucosa possesses the requisite hydrolytic, Phase II and efflux transporting 
enzymes necessary for local enteric recycling which would increase BRB-target tissue contact [12].
Collection of oral mucosa cells is relatively simple and such cells are an excellent source of 
material for evaluating DNA adducts derived from structurally varied carcinogens identified in tobacco 
smoke [24] and molecular alterations potentially related to cancer [6, 25-27].  In fact, Stepanov et al. 
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quantified NNN-induced HPB-releasing DNA adducts in oral cells (44.7 pmol/mg DNA) collected by 
buccal brushing and by mouth wash of smokers [28].  In nonsmokers HPB releasing DNA adducts were 
not detected.  A recent report demonstrated that NNN-induced DNA damage quantified in buccal cells 
was an independent risk factor for head and neck cancer [4]. Our preliminary results unequivocally 
demonstrate the presence of DNA adducts derived from B[a]P in buccal cells of smokers.  Such damage 
can provide a novel target for cancer prevention using agents such as BRB, which enhance repair of 
bulky DNA lesions [9, 10].  It has been reported that 8-OXO-dG levels were relatively stable over a one 
week period [6].  To our knowledge, only the HPB-releasing DNA adducts, acrolein-DNA adducts, and 8-
OXO-dG have been identified and quantified in human oral tissues.  Therefore, we will examine the 
effect of BRB on levels of DNA lesions derived from B[a]P, NNN; and also on 8-OXO-dG in buccal cells of 
smokers. Due to the extensive heterogeneity in human Phase 1/Phase II, oral microflora population, 
antioxidants and DNA repair activity, we expect that levels of DNA lesions in the oral cavity are likely to 
vary appreciably among current smokers.  Thus, we will compare the inhibitory effects of BRB on the 
levels of tobacco carcinogen-induced DNA damage in buccal cells in smokers at baseline and at the 
conclusion of our intervention on every participant which will enable intra- and inter-participant 
analysis.
3.0
Inclusion and Exclusion Criteria
3.1
 Inclusion Criteria
1.
Age 21-75
2.
Smoke 5 cigarettes per day or more for at least the past 12 months
3.
Have an expired air carbon monoxide measurement of greater than 6 parts per million
4.
Made no serious cigarette smoking quit attempt or have used any FDA-approved smoking 
cessation medication in the prior 30 days 
5.
Not planning to quit in the next 4 months
6.
Able to read and write in English
7.
Able to understand and provide consent to the study procedures
8.
Willingness and ability to attend regular visits over a 13-week and to respond to research 
contacts between visits
3.2
Exclusion Criteria
1.
Unstable or significant medical conditions that affect participant safety or biomarker data in the 
past 3 months (e.g. recent heart attack, asthma, COPD, cancer (except basal cell carcinoma of 
the skin), tumors (except if benign and excised participation), , neurodegenerative diseases, 
kidney failure, stroke, heart failure, uncontrolled angina, , uncontrolled high blood pressure, 
uncontrolled lung or respiratory disease, diabetes (except well-controlled type 2 diabetes), liver 
disease (except Hepatitis A), infectious disease, autoimmune disorder)
2.
Abnormalities found during oral cancer screening exam, including neoplastic and preneoplastic 
lesions
3.
Women currently pregnant or nursing
4.
Use of any non-cigarette nicotine delivery product in the past 7 days (e.g. e-cigarettes, pipe or 
cigar)
5.
Uncontrolled mental illness or substance abuse or inpatient treatment in the past 6 months
6.
Use of marijuana or other illegal drugs daily or weekly in the past 3 months
7.
Any known allergy to raspberries
8.
Use of high dose antioxidant supplements in the past month
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9.
Current use of antibiotics
10.
Heavy drinking (>4 drinks/day, 5 days/week)
11.
Currently in the process of reducing daily cigarette consumption or are planning to reduce the 
amount smoked in the next 3 months
12.
Any other condition that in the opinion of the investigator would make it unlikely that the 
participants could comply with the study protocol
3.3
Early Withdrawal of Subjects
3.3.1
Criteria for removal from study
Subjects will be informed that they may voluntarily drop out at any time. 
Participants will only be withdrawn from the study for the following reasons:
1.   New pregnancy: Participants who report a new pregnancy at any point during the study will 
be withdrawn.
2.   Suicide attempt:  If at any time during the study it is discovered that a participant has made a 
suicide attempt, they will be withdrawn from the study.
3.   New diagnosis of unstable or significant medical condition: Participants who are diagnosed 
with any of the medical exclusion conditions listed in section 3.2 during their participation in the 
study will be withdrawn due to the effect the condition may have on outcomes.
4.   Increase of alcohol use: Participant’s alcohol consumption increases to >4 drinks/day, 5 days 
or more per week  will be withdrawn from the study due to the effect it may have on biomarkers.
5.  Participant choice: Participants may choose to remove themselves from the study by 
informing the research team verbally or in writing at any point during the study
6.   Noncompliance: On a case to case basis, participants who repeatedly are non-compliant with 
the intervention (not using the BRB lozenge as intended on a daily basis) will be withdrawn from 
the study, as this will impact study outcomes.  
7.   Significant change in smoking rate from baseline: A participant will be withdrawn from the 
study if they either increase their weekly average cigarette use to 150% of baseline or decrease 
their weekly average cigarette use to 50% of baseline.
The PI will evaluate the participant for possible withdrawal from the study at any point for the 
following:
1.   Any hospitalization or debilitation in which participation in the study could be detrimental to 
the recovery process.  This will be self-reported by the participant and will be reviewed by the PI 
and medical professional to determine whether continued participation in the study is 
appropriate.
2.   Participant behavior: If a participant is behaving in an inappropriate or threatening manner, 
admits to lying about eligibility criteria, is participating in other smoking research studies that 
could affect the primary outcome measures, continually using other non-cigarette tobacco 
products, etc., then the PI can withdraw him/her from the study at the PI’s discretion.
3. Study visit window:  If a participant cannot attend their study visit within the study visit 
window then the PI can withdraw him/her from the study at the PI’s discretion.
3.3.2
Follow-up for withdrawn subjects
There will be no planned follow-up of withdrawn subjects. 
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4.0
Recruitment Methods
4.1
Identification of subjects
For subject recruitment, we will make use of our existing tobacco research recruitment system 
(STUDY00002213) and large database of tobacco research volunteers developed as part of our Penn 
State Tobacco Center of Regulatory Science (TCORS). This database includes over 3,500 individual 
smokers who have provided basic details on their tobacco use history and demographics as well as 
contact details. We plan to use this database to select and recruit eligible cigarette smokers to the 
proposed study. These subjects are primarily from the Hershey/Harrisburg area.  Additional recruitment 
will occur using our previously developed methods, including advertisements placed in local media 
(radio, newspapers, etc.), and through flyers, posters, and bulletin boards situated in close proximity to 
the Penn State Hershey Medical Center as outlined/uploaded in the IRB protocol STUDY00002213.  
Study flyers will be posted and distributed at the Bethesda Mission (Harrisburg, Pa). 
This study will also identify subjects through the Penn State Health electronic medical record.  Penn 
State EIM will release a data report of patients who have been diagnosed with nicotine dependence but 
without diabetes and those who have had a patient visit in the past 3 years.  The report will include 
patient contact information (i.e. phone number, email address, and address).  Researchers will reach out 
to potential participants through these avenues to let them know about the study opportunity.  
This study will utilize BuildClinical to help identify potential participants.  BuildClinical is a data-
driven platform that helps academic researchers recruit participants for research studies more 
efficiently using social media, software, and machine learning. They have worked with IRBs in the US to 
ensure they adhere to all the appropriate guidelines and procedures. They utilize already IRB approved 
study-specific advertisements to engage participants on digital platforms such as Facebook, Google, 
WebMD, etc. and redirect them to a study-specific landing page should they click it. On the landing 
page, the person can complete an online pre-screen questionnaire that gets routed into BuildClinical's 
platform. BuildClinical's Secure Socket Layer (SSL) software encrypts all inputted information and keeps 
information private and HIPAA compliant. 
4.2
Recruitment process
4.2.1
 How potential subjects will be recruited.
STUDY00002213  will serve as an initial recruitment point of contact for this study. Interested 
volunteers calling the study center number (located on all recruitment flyers) will go through an initial 
screening using STUDY00002213’s eligibility script. Questions will assess basic eligibility, i.e. age, 
smoking status, access to transportation, etc. All volunteers calling this line must give verbal consent 
prior to answering any questions. If the participant’s responses match our study’s specified inclusion 
criteria, they will be forwarded to us, and will be screened a second time (eligibility script uploaded 
under recruitment materials) for certainty of eligibility. All subjects calling in to either line will complete 
the initial screener under IRB#2213 first, and then complete the second screener under this study’s 
protocol.
Recruitment will include posting flyers (flyers have previously been approved under IRB 
STUDY00002213; they include images of people with the header “Do you smoke” and the study center’s 
number listed below) around the Harrisburg, Lancaster and York area, radio advertisements and media 
use. All materials used in our recruitment process have been approved by the IRB under 
STUDY00002213.  ResearchMatch.org will be utilized as a recruitment tool for this protocol.  
ResearchMatch.org is a national electronic, web-based recruitment tool that was created through the 
Clinical & Translational Science Awards Consortium in 2009 and is maintained at Vanderbilt University.  
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The ResearchMatch specific message is uploaded under Recruitment Materials.  Researchers will also 
identify potential participants from the EIM data report generated from the EMR.
Digital ads run by BuildClinical will include a link to a BuildClinical landing page that provides 
information about the study, eligibility, etc.  Once there, interested participants will click a link to go to a  
BuildClinical screening form that asks for contact information and basic study eligibility questions (a PDF 
of an example of a landing page and screening form have been uploaded for review).
4.2.2
Where potential subjects will be recruited.
Details on where participants will be recruited are in STUDY00002213.  Generally, subjects will 
be recruited from the surrounding counties, with a focus of identifying participants in the following 
counties: Dauphin, Lebanon, Cumberland, Lancaster and York. Potential participants will also be 
recruited through ResearchMatch.org and through BuildClinical’s services. 
4.2.3
When potential subjects will be recruited.
Details of when participants will be recruited are in IRB STUDY00002213. 
4.2.4
Describe the eligibility screening process and indicate whether the screening process will 
occur before or after obtaining informed consent. Screening begins when the investigator 
obtains information about or from a prospective participant in order to determine their 
eligibility.  In some studies, these procedures may not take place unless HIPAA Authorization 
is obtained OR a waiver of HIPAA Authorization when applicable for the screening procedures 
is approved by the IRB.  [For FDA regulated studies, consent for any screening activities would 
need to be obtained prior to screening unless specifically waived by the IRB.]
1. Call Routing Screener in IRB STUDY00002213 (Phone or online survey): We will consider the 
screening process and eligibility questions in IRB STUDY00002213 as Screening #1. This process 
includes a brief phone or online survey screening to determine basic eligibility for any of our study 
center protocols. Based on their answers to the questions participants will be routed to this study. 
Then, participants will complete the screening for this study in two additional steps.
2. Project Screener (Phone, email, or text): Participants will be contacted by researchers via 
phone, email, or text to complete the eligibility questions for the study.  Those contacted via phone 
will complete the screening questions over the phone with the researcher, while those contacted by 
email or text will be provided a REDCap link to complete the Eligibility survey online on their own. A 
full script and screening questions specific to this study are in the “Consent Forms and Recruitment 
Materials” section of the IRB application. If a participant has met basic eligibility criteria, they will be 
scheduled to come into the study center for their first visit.
3. Project Screener (In person at Visit 1): At Visit 1 they will be re-screened using the Project 
Screener (Phone). If the participant’s answers have changed from the phone screener and they are no 
longer eligible, they will be informed that they cannot participate. If they remain eligible, they will be 
consented to the study and further screened for eligibility. A full script and screening questions are 
uploaded in the “Consent Forms and Recruitment Materials” section of this IRB application.
5.0
Consent Process and Documentation 
 
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5.1
Consent Process:
Check all applicable boxes below:
 Informed consent will be sought and documented with a written consent form [Complete Sections 
5.2 and 5.6] 
 Implied or verbal consent will be obtained – subjects will not sign a consent form (waiver of 
written documentation of consent) [Complete Sections 5.2, 5.3 and 5.6] 
  Informed consent will be sought but some of the elements of informed consent will be omitted or 
altered (e.g., deception). [Complete section 5.2, 5.4 and 5.6] 
 Informed consent will not be obtained – request to completely waive the informed consent 
requirement. [Complete Section 5.5]
 
5.2
Obtaining Informed Consent 
5.2.1
Timing and Location of Consent 
When participants attend their first in-person visit, they will have the study explained to them in 
detail, have the opportunity to ask questions and then be asked to sign the consent form. 
Participants will be given a signed copy of the form. This will take place in a private clinic room 
at the Penn State Hershey Clinical Research Center (CRC). 
Consenting may also take place in a private space at the Bethesda Mission.
5.2.2
Coercion or Undue Influence during Consent 
The researchers obtaining consent will clearly indicate that the participant’s enrollment in the 
study is purely voluntary; the researchers will not offer comments about whether they believe 
the participant should enroll in the study or not. Given the number of contacts and visits 
involved in the study protocol, the compensation provided to the participant is modest. 
5.3
Waiver of Written Documentation of Consent 
5.3.1
Indicate which of the following conditions applies to this research:
  The research presents no more that minimal risk of harm to subjects and involves no 
procedures for which written consent is normally required outside of the research context.
OR
  The only record linking the subject and the research would be the consent document and the 
principal risk would be potential harm resulting from a breach of confidentiality. Each subject 
will be asked whether the subject wants documentation linking the subject with the research, 
and the subject’s wishes will govern. (Note: This condition is not applicable for FDA-regulated 
research. If this category is chosen, include copies of a consent form and /or parental 
permission form for participants who want written documentation linking them to the 
research.)
OR
  If the subjects or legally authorized representatives are members of a distinct cultural group 
or community in which signing forms is not the norm, that the research presents no more 
than minimal risk of harm to subjects and provided there is an appropriate alternative 
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mechanism for documenting that informed consent was obtained.  (Note: This condition is not 
applicable for FDA-regulated research.) 
Describe the alternative mechanism for documenting that informed consent was obtained:
For participants determined to be eligible, a study visit will be made where they will complete 
a written consent form.
5.3.2
Indicate what materials, if any, will be used to inform potential subjects about the research 
(e.g., a letter accompanying a questionnaire, verbal script, implied consent form, or summary 
explanation of the research)
 A verbal phone script will be used to inform potential subjects about the research and is 
uploaded with the screener under the Consent Form and Recruitment Materials section.
5.4
Informed consent will be sought but some of the elements of informed consent will be omitted or 
altered (e.g., deception).
5.4.1
Indicate the elements of informed consent to be omitted or altered
Not applicable
5.4.2
Indicate why the research could not practicably be carried out without the omission or 
alteration of consent elements
Not applicable
5.4.3
Describe why the research involves no more than minimal risk to subjects.
Not applicable
5.4.4
Describe why the alteration/omission will not adversely affect the rights and welfare of 
subjects.
Not applicable
5.4.5
If the research involves using identifiable private information or identifiable biospecimens, 
describe why the research could not be practicably be carried out without using such 
information or biospecimens in an identifiable format.
Not applicable
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5.4.6
Debriefing 
Not applicable
5.5
Informed consent will not be obtained – request to completely waive the informed consent 
requirement
5.5.1
Indicate why the research could not practicably be carried out without the waiver of consent
N/A
5.5.2
Describe why the research involves no more than minimal risk to subjects.
N/A
5.5.3
Describe why the alteration/omission will not adversely affect the rights and welfare of 
subjects.
N/A
5.5.4
If the research involves using identifiable private information or identifiable biospecimens, 
describe why the research could not be practicably be carried out without using such 
information or biospecimens in an identifiable format.
N/A
5.5.5
Additional pertinent information after participation
N/A
5.6
Consent – Other Considerations 
5.6.1
Non-English-Speaking Subjects
Non-English speaking subjects will not be eligible for this study. 
5.6.2
Cognitively Impaired Adults
5.6.2.1 Capability of Providing Consent
N/A.  Cognitively impaired adults will not be eligible for this study. 
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5.6.2.2
Adults Unable to Consent
N/A
5.6.2.3 Assent of Adults Unable to Consent
N/A
5.6.3
Subjects who are not yet adults (infants, children, teenagers) 
5.6.3.1 Parental Permission
Only adults are eligible for this study.
5.6.3.2 Assent of subjects who are not yet adults
Not applicable
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
6.1
Authorization and/or Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
Check all that apply:
 
Not applicable, no identifiable protected health information (PHI) is accessed, used or 
disclosed in this study. [Mark all parts of sections 6.2 and 6.3 as not applicable]
Authorization will be obtained and documented as part of the consent process. [If this is the 
only box checked, mark sections 6.2 and 6.3 as not applicable]
Partial waiver is requested for recruitment purposes only (Check this box if patients’ medical 
records will be accessed to determine eligibility before consent/authorization has been 
obtained). [Complete all parts of sections 6.2 and 6.3]
Full waiver is requested for entire research study (e.g., medical record review studies). 
[Complete all parts of sections 6.2 and 6.3]
Alteration is requested to waive requirement for written documentation of authorization 
(verbal authorization will be obtained). [Complete all parts of sections 6.2 and 6.3]
6.2
Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
6.2.1
Access, use or disclosure of PHI representing no more than a minimal risk to the privacy of the 
individual
6.2.1.1
Plan to protect PHI from improper use or disclosure
Information is included in the “Confidentiality, Privacy and Data 
Management” section of this protocol.
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6.2.1.2
Plan to destroy identifiers or a justification for retaining identifiers 
All study data will be retained indefinitely for any future analyses on the 
study population. 
6.2.2
Explanation for why the research could not practicably be conducted without access to and 
use of PHI
PHI must be collected to determine the participant’s eligibility in to the study. Some medical 
conditions listed in section 3.2, would exclude the participant from being eligible to participate. 
Contact information (name, phone number, address) will be used to follow-up about scheduling 
and for appointment reminders.  
6.2.3
Explanation for why the research could not practicably be conducted without the waiver or 
alteration of authorization
In order to screen the participants prior to inviting them into the study center, the study 
coordinator will conduct a phone screen to determine if the participant is eligible to participate 
in the study. 
6.3
Waiver or alteration of authorization statements of agreement
Protected health information obtained as part of this research will not be reused or disclosed to any 
other person or entity, except as required by law, for authorized oversight of the research study, or for 
other permitted uses and disclosures according to federal regulations.  
The research team will collect only information essential to the study and in accord with the ‘Minimum 
Necessary’ standard (information reasonably necessary to accomplish the objectives of the research) per 
federal regulations.  
Access to the information will be limited, to the greatest extent possible, within the research team. All 
disclosures or releases of identifiable information granted under this waiver will be accounted for and 
documented.
7.0
Study Design and Procedures
7.1
Study Design
This Phase 0 trial will consist of a 
single arm, where participants, 
after a 1-wk baseline period, will 
be placed on daily BRB (oral) 
lozenges for 8 wks followed by a 
4-wk washout.  Biological samples 
will be collected at 0, 1, 4, 5, 8, 9, 
12 and 13 wks (See figure).  An 8-
wk BRB administration period was 
selected based on previous clinical and preclinical data (1) and a 4-wk washout period is included to 
examine the effects of BRB withdrawal on major outcomes. 
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7.2
Study Procedures
Based on COVID-19 restrictions (Participant mask removal must PAUSE for all observational studies at 
the College of Medicine), the study team will mail or drop off buccal cell collection kits and exhaled CO 
monitoring devices to participants homes.  Participants will complete these study procedures before 
they come in for their scheduled study visit.  The participants will also be provided with instructional 
handouts for completing the study procedures.  If needed participants will be provided additional 
instruction through Zoom or phone.  With these adjustments in study procedures there will be no need 
for participants to take off their mask during study visits.  Once the restrictions are lifted, the study team 
will go back to collecting these samples during the study visit.
All clinical work will be conducted at the Smoking Research Laboratory in the Clinical Research Center 
and within the Dental Clinic Suite/PSH Medical Group (University Physician’s Center, Entrance 4) at Penn 
State College of Medicine in Hershey, PA.  Eligible subjects, after phone screening, will receive a study 
packet in the mail with directions to the clinic, a copy of the consent form, a Participant Medical History 
form, and a Participant Current Medications form to review and complete at home.  Participants will 
visit the clinic (Visit 1) for additional screening after obtaining informed consent, including measurement 
of exhaled carbon monoxide (CO), oral cancer examination (performed by Dr. Susan Mallery, DDS from 
the Ohio State University collaborative site, or a trained study team member and pregnancy test 
(females).  If the physician is not available at Visit 1, the oral cancer screening can be performed at Visit 
2.  Study team members who are trained to do the oral health exam can also complete the exam at Visit 
1 or 2.  Eligible subjects will be entered into the protocol where questionnaire data on demographics, 
medical history, lifestyle, tobacco and alcohol consumption, and usual dietary intake, biological samples 
(exfoliated buccal cells & urine) and anthropometric data will be collected. Subjects will return after 1 
wk (Visit 2, 2nd baseline) where biological samples will be collected and the test agent (BRB lozenge) will 
be supplied (includes a usage diary and instructions on the proper application).  At Visits 3 & 4 (Mid-test 
Phase, weeks 4 & 5) subjects will return unused product, complete a brief questionnaire on compliance 
and provide biological samples. At Visit 4, subjects will receive a new batch (4-week supply) of BRB 
lozenges.  At Visits 5 & 6 (End-test Phase, Weeks 8 & 9) subjects will return unused product, complete a 
brief questionnaire on compliance and provide biological samples. At Visit 6, subjects will return study 
diaries and enter the Washout Phase where no test agent will be provided. At Visits 7 & 8 (End-washout 
Phase, weeks 12 & 13), subjects will provide biological samples. The timing for collection of biological 
samples is based, in part, on the need for collecting ample quantities of DNA for analyses of carcinogen-
DNA adducts and 8-OXO-dG. Based on previous results and preliminary findings, DNA requirements are 
as follows: NNN-derived (HPB-releasing) adducts, 10 µg (5); B[a]P-derived adducts, 10 µg (preliminary 
data); 8-OXO-dG, 2 µg (104).  Typically, 20 µg of DNA can be isolated from exfoliated buccal mucosal 
cells collected according to the protocol outlined below, a value consistent with others (9, 105).  Thus, to 
assure that adequate levels of DNA are obtained, 2 sample collections (1 week apart) for each Phase of 
the study will be obtained as follows: Baseline Phase (weeks 1 & 2); Mid-test Phase (weeks 4 & 5); End-
test Phase (weeks 8 & 9); End-washout Phase (weeks 12 & 13).  The 1-week waiting period between 
sampling is consistent with the 5-7 day turnover rate for the buccal epithelium (106) allowing for 
adequate recovery of cells and avoids potential bias towards collection of differentially affected cell 
populations (cell surface vs. underlying cells) (9, 106).  All subjects will be remunerated for their 
participation ($300 in total; $25/visit and an additional $100 at the final visit).
 
Phone 
Screening
Enrollment/
Baseline
BRB Intervention
BRB Washout
Study Visit #
1
2
Phone 
Call 1
3
4
Phone 
Call 2
5
6
Phone 
Call 3
7
8
Study Week #
-1
0
1
2.5
4
5
6.5
8
9
10.5
12
13
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Measures/Questionnaires
Eligibility Questions 
Screener
X
X
Name Registry
X
Informed consent
X
Medical history
X
Concomitant medications
X
Oral Cancer Screening 
X
Demographics
X
Cigarette Details
X
Cigarette Dependence
X
Menstrual Cycle
X
X
X
X
X
X
X
X
Product Evaluation
X
Dietary intake interviews 
(between visits)
X
X
BRB Dispensation
X
X
Daily Study Log
X
X
X
X
X
X
X
Adverse Event Trigger 
questions/ Adverse Event 
Log
X
X
X
X
X
X
X
Biomeasures
Height
X
Weight
X
X
X
X
X
X
X
X
Exhaled CO
X
X
X
X
X
X
X
X
Blood pressure/pulse
X
X
X
X
X
X
X
X
Pregnancy test
X
X
X
X
Buccal cells collection
X
X
X
X
X
X
X
X
Urine collection
X
X
X
X
7.2.1
Visits 1 & 2. 
Baseline Phase: (Visits 1 & 2, Weeks 0 & 1). Recruited subjects will visit the clinic twice during 
this phase at week 0 and week 1. At visit 1, eligible subjects will come to the Dental Clinic 
Suite/PSH Medical Group (University Physician’s Center, Entrance 4) or the Clinical Research 
Center. The research coordinator will complete the screener again to ensure answers did not 
change.  The coordinator will review the informed consent with the participant and go over any 
inquiries the participant may have. After consent, medical history and current concomitant 
medications will be reviewed (participants will be prompted when scheduling their first study 
visit to either bring in a list or the bottles of their current medication/s).  Next, an oral cancer 
screening (performed by Dr. Susan Mallery, DDS from the Ohio State University, collaborative 
site, or a trained study team member) will occur.  Study team members who are trained to do 
the oral health exam can also complete the exam at Visit 1 or 2.  If, upon screening, a subject is 
found to have a suspicious oral lesion or abnormality, they will be removed from the study and 
referred to their personal physician for follow-up.  The details of the suspicious oral lesion or 
abnormality will be provided to the subject using the Medical Professional letter.  If needed, a 
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list of low cost dental and health clinics in the area will also be provided to the subject.   The oral 
cancer screening can be done at Visit 2 if the physician is not available on the day of Visit 
1.Participants will complete a urine sample (for pregnancy determination for women of child-
bearing potential, i.e. those who have had a period in the past 12 months and who have not had 
a hysterectomy), exhaled CO (by a piCO+ Smokerlyzer), blood pressure, heart rate, height and 
weight during the visit. Participants will provide an exfoliated buccal mucosal cell sample 
obtained by using a procedure we have previously used and optimized for maximum DNA yield 
(72, 121).  Subjects will rinse their mouth with distilled water before collection of the buccal 
cells and then gently brush the inside of their cheeks (both sides) with a soft bristle toothbrush. 
The mouth is then rinsed with saline for 2-3 minutes and participants will expectorate the 
solution into a collection tube.  The toothbrush will be agitated in the collection tube.  The 
participant may be taken to a private patient room in the IO Silver Heart and Vascular Practice 
Clinic in the University Physicians Center (UPC, Suite 600) to complete part of the study visit. 
Female participants will be asked on a continual monthly basis to report dates of their menstrual 
cycle for biomarker purposes.  Participants will be sent their baseline questionnaires via a survey 
link to fill out at home after the visit.  These include Demographics, Cigarette Dependence, and 
Cigarette Details.  Participants will be encouraged to fill them out before their next visit.  All 
participants will be provided a daily study log to complete independently to tally the number of 
cigarettes smoked per day and number of alcoholic drinks. During the baseline phase, 2 
unannounced 24-food recall assessments will be conducted by trained dieticians through the 
BioNutritional Service of the Penn State Clinical Research Center to obtain information regarding 
dietary intake of phytochemicals. 
At Visit 2, participants will have measurements and biosamples taken, including a urine sample, 
exhaled CO, heart rate, blood pressure, and weight. Additionally, the participant will provide an 
exfoliated buccal mucosal cell sample as described above.  Participants will be asked for their 
daily study log from the week prior.  Participants will be asked about adverse events using the 
Adverse Event Trigger questions.  At this time, all participants will receive a four week supply of 
BRB lozenges and be instructed to consume 1 lozenge, 5 times/day by placing the lozenge in 
their mouth and slowly sucking on it until fully dissolved (~10-12 min).  Participants will be asked 
to consume their first lozenge while at the clinic to ensure proper usage.  Participants will be 
instructed to not eat or drink 15 minutes following lozenge use.  Along with the lozenges, 
participants asked to complete independently a daily study log to tally all lozenges, alcoholic 
drinks, and cigarettes consumed per day.
7.2.2
Visits 3 & 4
Mid-test (Mid-BRB administration) Phase: (Visits 3 & 4, Weeks 4 & 5).  At Visits 3 & 4, 
participants will return unused product and complete a brief questionnaire on compliance and 
adverse events, including possible changes in medication and health status. Females will be 
asked to report the date of their last menstrual cycle as changes can affect biomarkers.  The 
coordinator will collect the BRB lozenges and daily study log for review.  The coordinator will 
review any uncaptured cigarette or lozenge usage data not recorded on the daily log. Then, 
measurements and biosamples will be taken, including a urine sample (Visit 4 only), exhaled CO, 
blood pressure, heart rate, and weight. A urine pregnancy test will be completed at Visit 4.  
Additionally, the participant will provide an exfoliated buccal mucosal cell sample at Visits 3 and 
4.  At Visit 4, subjects will receive a new batch (4-week supply) of BRB lozenges along with new 
log (if needed) for cigarette, alcohol, and lozenge usage. 
7.2.3
Visits 5 & 6. 
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End-test (End BRB administration) Phase: (Visits 5 & 6, Weeks 8 & 9).  At Visits 5 & 6, 
participants will return unused product and complete a brief questionnaire on compliance and 
adverse events, including possible changes in medication and health status. Females will be 
asked to report the date of their last menstrual cycle as changes can affect biomarkers.  A urine 
pregnancy test will be completed at Visit 6. The coordinator will collect the BRB lozenges and 
daily study log. The coordinator will review any uncaptured cigarette or lozenge usage data not 
recorded on the daily log. Then, measurements and biosamples will be taken, including a urine 
sample (Visit 6 only), exhaled CO, blood pressure, heart rate, and weight. Additionally, the 
participant will provide an exfoliated buccal mucosal cell sample at Visits 5 and 6.  At Visit 6, 
subjects will enter the washout period where no more BRB lozenges will be provided. 
Participants will receive a new daily study log (if needed) to record cigarette and alcohol use in 
the next phase.  During the last week of the BRB administration period, 2 unannounced 24-food 
recall assessments will be conducted by trained dieticians through the BioNutritional Service of 
the Penn State Clinical Research Center to obtain information regarding dietary intake of 
phytochemicals.  
7.2.4
Visits 7 & 8. 
End-washout Phase: (Visits 7 & 8, Weeks 12 & 13). At Visits 7 & 8, participants will complete a 
brief questionnaire (BRB AE Trigger Questions) on adverse events, and possible changes in 
medication and health status. Females will be asked to report the date of their last menstrual 
cycle.  A urine pregnancy test will be completed at Visit 8.  The coordinator will collect the daily 
study log.  The coordinator will review any uncaptured cigarette usage data not recorded on the 
daily study log. Then, measurements and biosamples will be taken, including a urine sample 
(Visit 8 only), exhaled CO, blood pressure, heart rate, and weight. Additionally, the participant 
will provide an exfoliated buccal mucosal cell sample at Visits 7 and 8.  
7.2.5
Phone Interviews 
Since there is a 3-week gap between Visits 2 & 3, and Visits 4 & 5, and 6 & 7, the coordinator will 
contact the participant midway through the off clinic weeks to determine if the participants are 
having any issues with compliance and to remind them of their next scheduled visit.  The 
coordinator will document in Redcap whether or not they are able to get a hold of the subject.
7.3
Duration of Participation
Subjects will be in the study for a total of 13 weeks.  This will include 8 clinic visits which should typically 
last 30-45 mins each.  
7.4
Test Article(s) (Study Drug(s) and/or Study Device(s))
7.4.1
Description
The test agent will be freeze-dried black raspberry in the form of a dissolvable slow-release 
lozenge.  This product is available over-the-counter without prescription 
(https://www.berrihealth.com/collections/frontpage/products/authentic-1000-mg-black-
raspberry-lozenges-bottle-of-30).  See attachment (BRB lozenge label) for layout of the bottle 
label. Each lozenge contains 1 gram (g) BRB freeze-dried powder equivalent to ~5 black 
raspberries and will be purchased from BerriProducts LLC, Corvallis, OR.  A similar dosage 
regimen has been used in a previous trial.[11]  All lozenges will be prepared from a single 
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harvest/year lot of black raspberries obtained from Corbett and Sandy Oregon (see BRB 
Certificate of Analysis and BRB COA Letter).  The plants are Rubus occidentalis of the Munger 
cultivar. This form of BRB administration was selected over other forms previously used, 
including consumption in diet or application in gels, based on ease of use, the ability to more 
accurately control dose to target tissue, and a prolonged oral mucosa contact time facilitating 
bioactive component delivery. Lozenges will be packaged in Polyethylene terephthalate (PETE) 
tamper proof bottles with oxygen absorbers and desiccants.  The shelf life is more than 3 yrs 
when unopened and 3 months after opening at normal room conditions. Immediately after we 
receive the lozenges, they will be analyzed for composition and stability of their constituents.  
No toxicity has been associated with freeze-dried black raspberry powder.  In a 9 month study in 
rats, freeze-dried black raspberry powder in the diet at levels equivalent to 1.8 oz per day 
(representing approximately 1.2 lb of raspberries per day in humans) was not associated with 
any signs of toxicity. [29] 
7.4.2
Intervention Regimen
A dose of 5 g freeze-dried BRB per day will be provided to each participant in the form of 
dissolvable slow-release BRB lozenges (each containing 1 g BRB freeze-dried powder) 
(BerriProducts LLC, Corvallis, OR).  Each subject will consume 1 lozenge, 5 times/day and 
instructed to not eat or drink 15 minutes following lozenge use.    
7.4.3
Method for Assigning Subject to Intervention Groups
In this Phase 0 trial, all subjects will receive the same intervention.
7.4.4
Subject Compliance Monitoring
Adherence to the study protocol will be assessed by analysis of diary entries and comparison of 
returned BRB lozenges. 
7.4.5
Blinding of the Test Article
This will not be a blinded study.
7.4.6
Receiving, Storage, Dispensing and Return 
7.4.6.1
Receipt of Test Article 
BRB lozenges will be obtained from BerriProducts LLC, Corvallis, OR.  They 
will be shipped in boxes to Penn State Hershey directly. Lozenges will be 
packaged in PETE tamper proof bottles containing 30 lozenges with oxygen 
absorbers and desiccants.  
7.4.6.2
Storage
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The test agents will be stored in a refrigerator in the PSU Tobacco Center 
pharmacy. We will monitor and record the temperature of the refrigerator. 
7.4.6.3
Preparation and Dispensing
The research coordinator will be responsible for preparing and distributing 
the lozenges to participants. Lozenges will be prepared for distribution in 
the PSU Tobacco Center pharmacy.  Research coordinator will prepare a 
package with the appropriate allotment of BRB lozenges the participant 
will need until the next study visit. 
7.4.6.4
Return or Destruction of the Test Article
Any unused lozenges that are returned from the participant will be 
counted and destroyed on site.
7.4.6.5
Prior and Concomitant Therapy
Concomitant medications will be surveyed at all study visits to serve as 
covariates during analysis and to monitor participant health conditions. 
Medications related to certain medical conditions that are exclusions to 
the study will serve to alert the study staff of the presence of these 
conditions during screening.
8.0
Subject Numbers and Statistical Plan
8.1
Number of Subjects
75 subjects will be enrolled to account for participants who drop out of the study. A total of 47 will be 
needed to complete the research procedures.  
8.2
Sample size determination
We are unware of any published data about the intervention effect on the primary endpoint. But the 
huge difference between smokers and non-smokers in Stepanov et al (63) suggests a huge potential for 
intervention effect. For the sample size calculation, we assume that 70% of subjects will have lower 
HPB-releasing adduct values from beginning to end of a considered period and 30% will have a higher 
values. We will test the hypothesis that 50% of subjects will have a lower values and 50% will have 
higher values. It then follows that 47 subjects provides 80% power at 5% type I error.  In the case of 75% 
of subjects having a lower value and 25% have a higher value, 30 subjects are required.  For this study, 
we will use 47 subjects to ensure sufficient power and will recruit 75 subjects (an additional 28 to 
account for potential drop-outs). 
8.3
Statistical methods
The main endpoints of this trial are the carcinogen-induced HPB-releasing adducts and secondarily, 
B[a]P-DNA adducts and 8-OXO-dG in buccal cells. The statistical analysis will focus on the difference 
between measurements at baseline (wks 1 & 2) and after BRB intervention (wks 8 & 9). Based upon the 
lack of preliminary data on inter-individual variation of B[a]P-DNA adducts and the known importance of 
HPB-releasing adducts on carcinogenesis (4), we have focused on this latter outcome as the primary 
endpoint.  Stepanov et al (63) provides data on HPB-releasing adducts which show a drastic difference 
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between smokers (mean [SD]=12.0 [35.1], n=30) and non-smokers (0.23 [0.43], n=15). The distribution 
of these adducts for smokers severely deviated from normality, with the majority of values at lower end 
(<5), but a few at high end (>15). For this reason, the Wilcoxon rank test will be used to analyze the 
change pre- and post-BRB intervention.  In addition, boxplots of HPB-releasing adducts at beginning of 
and end of BRB intervention and of resultant changes will be used to summarize the information. The 
other endpoints are expected to show similar distributions, so the same analysis strategy will be used.  
Paired t-test will be used for endpoints that are approximately normally distributed. Additionally, 
outcome measurements at different time points (baseline, 4-5 wk, 8-9 wk, and at the end (12-13 wk 
after BRB initiation, 4 wk after withdrawal of BRB), after appropriate transformation, will be modeled 
using linear mixed effects to study their change over time after BRB administration where appropriate.
9.0
Data and Safety Monitoring Plan
9.1
Periodic evaluation of data
The PI of the project will be responsible for monitoring the overall safety and integrity of the research 
project with the assistance of the study coordinator. Participants will meet during regularly scheduled 
visits with the coordinator who will assess adverse events throughout the study. If there are any 
concerns on participant safety, they will be brought to the PI’s attention. Dr. El-Bayoumy will meet 
monthly and as needed with the study staff to review data, including any adverse events.
The Penn State Cancer Institute Data and Safety Monitoring Committee (PSCI DSMC) will be the Data 
and Safety Monitoring Board of record.  The PSCI DSMC will review adverse event reporting and data 
and safety monitoring through annual study progress reports submitted by the study team.
9.2
Data that are reviewed
Data that will be included in the study progress reports and reviewed by the PSCI DSMC include:
• Accrual and retention
• Subject enrollment status
• Participant demographic information
• Protocol deviations/violations
• Adverse events summary 
9.3
Method of collection of safety information
All safety data will be directly coded into REDCap during study visits.  At each visit after visit 1, 
participants will be asked a series of non-directive questions that would trigger an assessment for an 
adverse event to be documented. An adverse event will also be documented if a participant volunteers 
information about changes in their health at a study visit. An adverse event log (uploaded in the 
Supporting Documents section) will be used to document the description of the adverse event, including 
start/stop dates, type, grade, relationship to the study and action taken. 
9.4
Frequency of data collection
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Questions assessing adverse events will be collected at each visit after visit 1 and may also be collected 
when the participant volunteers information between visits (e.g. compliance reminder phone calls). 
9.5
Individuals reviewing the data
The PI of the project will be responsible for monitoring the overall safety and integrity of the research 
project with the assistance of the study coordinator. The study coordinator will be responsible for the 
daily oversight of the study and recording all AEs. Dr. Susan Mallery, PhD, DDS (Professor and Chair, 
Division of Pathology and Radiology, The Ohio State University College of Dentistry, collaborative site) 
will review AEs with the study coordinator as needed.  
The PSCI DSMC and the Committee’s appointed Medical Monitor, Dr. Shin Mineishi, will review the 
annual study progress reports.  If a serious AE occurs the study team will notify the PSCI DSMC as soon 
as possible.  The serious AE will be reviewed by the Medical Monitor and PSCI DSMC.
9.6
Frequency of review of cumulative data
The PSCI DSMC and the Committee’s appointed Medical Monitor, Dr. Shin Mineishi, will review the 
study progress reports annually.  If a serious AE occurs the study team will notify the PSCI DSMC as soon 
as possible.
9.7
Statistical tests
Basic summary data will be compiled to report the study accrual, dropout rate, completion rate, and the 
proportions of adverse events.   
9.8
Suspension of research
Due to the low risk of the study intervention, it is unlikely that there will be a need to suspend the 
research. However, should the PSCI DSMC identify any issues after reviewing the data, these 
recommendations will be followed.
10.0
Risks
A potential risk with using the black raspberry lozenges is stomach discomfort (i.e. nausea/vomiting), especially for 
people with certain stomach sensitives to berries.  Other potential risks to subject volunteers in this study will be 
minimal as all sampling is non-invasive.  There is the potential for minor irritation from the collection of exfoliated buccal 
mucosal cells which involves brushing the inside of the mouth with a soft toothbrush.  There is minimal risk of breach of 
confidentiality in this study.  Precautions will be taken to prevent this, including direct coding of data in REDCap.  It is 
possible that some of the questions in the questionnaires may make participants uncomfortable.  They will be instructed 
that they are free to skip any questions that make them uncomfortable.
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11.0
Potential Benefits to Subjects and Others 
11.1
Potential Benefits to Subjects
None
11.2
Potential Benefits to Others
Society as a whole will benefit from the research because it is expected to provide important 
information on the effectiveness of BRB to reduce DNA damage resulting from cigarette smoking. 
Cigarette smoke is the leading preventable cause of disease and current evidence-based interventions 
are ineffective for many current smokers. The study should provide empirical data on whether BRB 
intervention may be a valid disease prevention approach for addicted smokers.  
12.0
Sharing Results with Subjects
The study is not designed to diagnose or treat any disease or condition.  If during the course of conducting 
clinical procedures (e.g., blood pressure) a participant is found to have a result outside of clinical norms, the 
result will be discussed with the participant at the visit where the result is identified.  If during the oral exam any 
abnormalities or issues are found, the observation will be shared with the participant and they will be advised to 
follow up with their dentist or doctor.  Pregnancy tests will be given to female participants at the initial 
screening visit and throughout the study. If the test is positive, the results will be shared with the participant and 
they will be advised to follow up with their doctor. They will not be allowed to participate in the study. No 
results will be shared with others, such as the participant’s Primary Care Provider.
13.0
Subject Payment and/or Travel Reimbursements
Subjects will receive a nominal payment of $35 each visit completed for visits 1 - 8, and an additional $100 at the 
final visit.   Total possible payment is $380 and covers traveling to site, buccal cell and urine samples and for 
their time and participation. Payments will be issued on the Greenphire ClinCard.
14.0
Economic Burden to Subjects
14.1
Costs
The only cost associated with participation in the research is travel to and from the clinic on clinic visit 
days.  Reimbursement for these costs is included in the participant’s stipend.
14.2
Compensation for research-related injury
It is the policy of the institution to provide neither financial compensation nor free medical treatment 
for research-related injury. In the event of injury resulting from this research, medical treatment is 
available but will be provided at the usual charge. Costs for the treatment of research-related injuries 
will be charged to subjects or their insurance carriers. 
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15.0
Resources Available 
15.1
Facilities and locations
All clinical work will be conducted at the Dental Clinic Suite/PSH Medical Group (University Physician’s 
Center, Entrance 4) and the Smoking Research Laboratory in the Clinical Research Center at Penn State 
College of Medicine in Hershey, PA.  
The Bethesda Mission will be used as a site to conduct the study.
15.2
Feasibility of recruiting the required number of subjects
Recruitment is open to all smokers meeting inclusion and exclusion criteria. Favorable word of mouth 
from smoking participants to their family/friends/coworkers has served as a significant source of 
recruitment in past research studies. Feasibility of acquiring participants is very good. Additionally, the 
estimated smoking prevalence in 2017 in Pennsylvania was 19% which is higher than the national 
average.  
15.3
PI Time devoted to conducting the research
PI has committed 5% FTE in years 1-5 for the project. 
15.4
Availability of medical or psychological resources
It is not anticipated that participants will need any medical or psychological resources as a result of 
being in this study. Safety of the participants will be monitored throughout the study. 
15.5
Process for informing Study Team
All members of the study team have completed IRB/CITI/GCP training; documentation of such has been 
submitted to the IRB. The PI and study coordinator will train additional personnel when needed  on 
protocol procedures. 
16.0
Other Approvals
16.1
Other Approvals from External Entities
Dr. Richie’s lab is approved under the Institutional Biosafety Committee JPR12-01-2 for work with 
human body fluids. Dr. El-Bayoumy’s lab (co-investigator) is also approved under the Institutional 
Biosafety Committee (KEE20-01-2) for work with human body fluids. In addition, the study will be 
registered on clinicaltrials.gov. 
16.2
Internal PSU Committee Approvals
Check all that apply:
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  Anatomic Pathology – Penn State Health only – Research involves the collection of tissues or use of 
pathologic specimens. Upload a copy of “HRP-902 - Human Tissue For Research Form” in CATS IRB. 
  Animal Care and Use – All campuses – Human research involves animals and humans or the use of 
human tissues in animals
  Biosafety – All campuses – Research involves biohazardous materials (human biological specimens 
in a PSU research lab, biological toxins, carcinogens, infectious agents, recombinant viruses or DNA 
or gene therapy).
  Clinical Laboratories – Penn State Health only – Collection, processing and/or storage of extra tubes 
of body fluid specimens for research purposes by the Clinical Laboratories; and/or use of body fluids 
that had been collected for clinical purposes but are no longer needed for clinical use. Upload a copy 
of “HRP-901 - Human Body Fluids for Research Form” in CATS IRB. 
  Clinical Research Center (CRC) Advisory Committee – All campuses – Research involves the use of 
CRC services in any way.
  Conflict of Interest Review – All campuses – Research has one or more of study team members 
indicated as having a financial interest.
  Radiation Safety – Penn State Health only – Research involves research-related radiation 
procedures. All research involving radiation procedures (standard of care and/or research-related) 
must upload a copy of “HRP-903 - Radiation Review Form” in CATS IRB. 
  IND/IDE Audit – All campuses – Research in which the PSU researcher holds the IND or IDE or 
intends to hold the IND or IDE.
  Scientific Review – Penn State Health only – All investigator-written research studies requiring 
review by the convened IRB must provide documentation of scientific review with the IRB 
submission. The scientific review requirement may be fulfilled by one of the following: (1) external 
peer-review process; (2) department/institute scientific review committee; or (3) scientific review by 
the Clinical Research Center Advisory committee.  NOTE: Review by the Penn State Health Cancer 
Institute (PSCI) Protocol Review Committee or the PSCI Disease Team is required if the study 
involves cancer prevention studies or cancer patients, records and/or tissues. For more information 
about this requirement see the IRB website.
17.0
Multi-Site Study
 
17.1
Other sites 
Collaborative Site:  The Ohio State University College of Dentistry, Columbus, OH.
Site PI:  Susan Mallery, DDS, MS, Ph.D., Professor and Chair, Division of Oral and Maxillofacial 
Pathology and Radiology.  
Contact Information:  2191-B Postle Hall, 305 W. 12th Ave, Columbus, OH 43210.  Phone: 614-292-5892.  
Email: mallery.1@osu.edu.
IRB:  Ohio State University Biomedical Sciences IRB  
17.2
Communication Plans
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There will be no subject recruitment occurring at the Ohio State University site as all subjects will be 
recruited at Penn State University.  Dr. Mallery’s role will be to provide support for the clinical trial by 
assisting with review of adverse events and to provide oral cancer  screenings of participants.  There will 
be direct lines of communication between the Penn State NIH-funded grant PI (Dr. El-Bayoumy) and the 
Ohio State University PI, Dr. Mallery.  There will be no other Ohio State personnel involved in this study.  
Dr. Mallery will participate in bi-weekly study meetings attended by all study personnel where progress, 
issues and problems will be discussed.  AE’s will be communicated with Dr. Mallery in an immediate 
fashion as described in the study protocol.  Dr. El-Bayoumy will be in charge of ensuring that IRB 
approval has been obtained from both institutes and for the prompt distribution of the most current 
protocols, consent forms, etc. through direct communication with Dr. Mallery.
17.3
Data Submission and Security Plan
All raw data from the study will be maintained at the Penn State University site. Identifiable information 
shared with Dr. Mallery will be kept to a minimum.  If identifiable or health information needs to be 
shared with Dr. Mallery it will be password protected.  
17.4
Subject Enrollment
There will be no subject enrollment at the Ohio State University site.
17.5
Reporting of Adverse Events and New Information
N/A
17.6
Audit and Monitoring Plans
N/A
18.0
Adverse Event Reporting
18.1
Adverse Event Definitions
For drug studies, incorporate the following definitions into the below responses, as written:
Adverse event
Any untoward medical occurrence associated with the use of the drug in 
humans, whether or not considered drug related
Adverse reaction
Any adverse event caused by a drug
Suspected adverse 
reaction
Any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event.  Suspected adverse reaction implies a lesser degree 
of certainty about causality than “adverse reaction”.

Reasonable possibility.  For the purpose of IND safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.
Serious adverse 
event or Serious 
suspected adverse 
reaction
Serious adverse event or Serious suspected adverse reaction: An adverse event 
or suspected adverse reaction that in the view of either the investigator or 
sponsor, it results in any of the following outcomes: Death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions, or a congenital anomaly/birth 
defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the patient or 
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subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
Life-threatening 
adverse event or 
life-threatening 
suspected adverse 
reaction
An adverse event or suspected adverse reaction is considered “life-
threatening” if, in the view of either the Investigator (i.e., the study site 
principal investigator) or Sponsor, its occurrence places the patient or research 
subject at immediate risk of death.  It does not include an adverse event or 
suspected adverse reaction that had it occurred in a more severe form, might 
have caused death.
Unexpected 
adverse event or 
Unexpected 
suspected adverse 
reaction.  
An adverse event or suspected adverse reaction is considered “unexpected” if 
it is not listed in the investigator brochure, general investigational plan, clinical 
protocol, or elsewhere in the current IND application; or is not listed at the 
specificity or severity that has been previously observed and/or specified.
For device studies, incorporate the following definitions into the below responses, as written:
Unanticipated 
adverse device 
effect
Any serious adverse effect on health or safety or any life-threatening problem 
or death caused by, or associated with, a device, if that effect, problem, or 
death was not previously identified in nature, severity, or degree of incidence 
in the investigational plan or IDE application (including a supplementary plan 
or application), or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects.
18.2
Recording of Adverse Events
Research subjects will be questioned on possible adverse events at study visits 2-8. An adverse event 
may also be collected if the participant volunteers information between visits, for example, during their 
phone call check-ins. 
All adverse events (serious or non-serious) and abnormal test findings observed or reported to the study 
team believed to be associated with the study drug will be followed until the event, its sequelae, or the 
abnormal test finding resolves or stabilizes at a level acceptable to the investigator. 
An abnormal test finding will be classified as an adverse event if one or more of the following criteria are 
met:
•
The test finding is accompanied by clinical symptoms.
•
The test finding necessitates additional diagnostic evaluation(s) or medical/surgical intervention, 
including significant additional concomitant drug treatment or other therapy. Note: Simply 
repeating a test finding, in the absence of any of the other listed criteria, does not constitute an 
adverse event.
•
The test finding leads to a change in study drug dosing or discontinuation of subject participation in 
the clinical research study.
•
The test finding is considered an adverse event by the investigator. 
18.3
Causality and Severity Assessments
The investigator will promptly review documented adverse events and abnormal test findings to 
determine 1) if the abnormal test finding should be classified as an adverse event; 2) if there is a 
reasonable possibility that the adverse event was caused by the study drug(s) or device(s); and 3) if the 
adverse event meets the criteria for a serious adverse event.
If the investigator’s final determination of causality is “unknown and of questionable relationship to the 
study drug(s) or device(s)”, the adverse event will be classified as associated with the use of the study 
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drug(s) or device(s) for reporting purposes.  If the investigator’s final determination of causality is 
“unknown but not related to the study drug(s) or device(s)”, this determination and the rationale for the 
determination will be documented in the respective subject’s case history.
18.4
Reporting of Adverse Reactions and Unanticipated Problems to the FDA  
18.4.1 Written IND/IDE Safety Reports
N/A
18.4.2 Telephoned IND Safety Reports – Fatal or Life-threatening Suspected Adverse Reactions
N/A
18.5
Reporting Adverse Reactions and Unanticipated Problems to the Responsible IRB
In accordance with applicable policies of The Pennsylvania State University Institutional Review Board 
(IRB), the investigator will report, to the IRB, any observed or reported harm (adverse event) 
experienced by a subject or other individual, which in the opinion of the investigator is determined to be 
(1) unexpected; and (2) probably related to the research procedures. Harms (adverse events) will be 
submitted to the IRB in accordance with the IRB policies and procedures.
18.6
Unblinding Procedures
N/A
18.7
Stopping Rules
No formal a priori statistical stopping rules will be used for interim monitoring of the primary or 
secondary endpoints. Analyses will be performed and comprised of endpoints associated with safety 
and study integrity (i.e. recruitment rate, completion rate, rates of SAEs/AEs), and any other variables 
that are requested from the Penn State Cancer Institute Data and Safety Monitoring Committee. An 
annual summary report of this information will be prepared by the study team for the committee to 
review.  The committee will use these reports as the primary basis assessing data quality and subject 
safety, and if necessary making recommendations of amendment to the protocol or stopping the trial.
19.0
Study Monitoring, Auditing and Inspecting
19.1
Study Monitoring Plan
19.1.1 Quality Assurance and Quality Control
 
Study data will be managed using REDCap (Research Electronic Data Capture). REDCap is a 
secure web application designed to support data capture for research studies, providing user-
friendly web-based case report forms, real-time data entry validation (e.g. for data types and 
range checks), audit trails and a de-identified data export mechanism to common statistical 
packages (SPSS, SAS, Stata, R/S-Plus). The system was developed by a multi-institutional 
consortium which includes The Pennsylvania State University and was initiated at Vanderbilt 
University. The database is hosted at the Penn State Health Medical Center and College of 
Medicine data center, which will be used as a central location for data processing and 
management. REDCap data collection projects rely on a thorough study-specific data dictionary 
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defined in an iterative self-documenting process by all members of the research team. This 
iterative development and testing process results in a well-planned data collection strategy for 
individual studies. 
REDCap is HIPAA compliant. Data are stored on a secure server; data in REDCap are encrypted; 
access to the database requires authentication (a unique username and password); data are 
accessed based on the individual’s role on the project; every interaction with the data is logged, 
creating an audit trail.
Data quality tools included in REDCap will be utilized to identify incorrect data types, out of 
range data and outliers in real-time.
19.1.2 Safety Monitoring
The Principal Investigator (Dr. El-Bayoumy) will confirm that AEs are entered into the AE case 
report forms by the coordinator; and will notify the IRB, sponsor and/or DSMC of all applicable 
AEs as appropriate.   
The Co-Investigator (Dr. Susan Mallery) will be available to answer any questions that the 
coordinators may have concerning AEs; make final assessments of causality of AEs.
The Research Coordinator will complete appropriate report forms and adverse event logs; assist 
the PI to prepare reports and notify the IRB, sponsor and/or DSMC of all applicable AEs as 
appropriate. 
The Medical Monitor appointed by the PSCI DSMC is Dr. Shin Mineishi.  He will review annual 
reports submitted to the PSCI DSMC and will be contacted for any urgent safety matters during 
the study.
20.0
Future Undetermined Research: Data and Specimen Banking
20.1
Data and/or specimens being stored
Urine and exfoliated buccal mucosal cell samples will be banked for future undetermined research. 
Specimens will be stored with an ID code attached. All data associated with the ID code will be retained 
in REDCap.
20.2
Location of storage
Specimens will be stored in a locked freezer room in the research laboratory on the
3rd floor of the Cancer Institute. All data will be stored in REDCap. 
20.3
Duration of storage
Specimens will be stored indefinitely with code number attached. Data will be stored indefinitely with 
identifiers attached in REDCap. 
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20.4
Access to data and/or specimens
The lab managers will have access to the locked freezer room where the specimens will be stored. The 
research coordinators will have access to the stored data in REDCap. 
20.5
Procedures to release data or specimens
Investigators who are interested in obtaining samples from this project for ancillary studies will first be 
required to submit a detailed written proposal to Dr. El-Bayoumy. Dr. El-Bayoumy will then review the 
proposal and, if approved, the investigator will be required to obtain all other regulatory approvals (IRB, 
departmental scientific committees, etc.) prior to samples being released. Only de-identified data, as 
approved in the investigator’s IRB application, will be released to the investigator. 
20.6
Process for returning results
Investigators will be required to provide a written report on their study results to the PI.
21.0
References
See bibliography 
22.0
Confidentiality, Privacy and Data Management 
IMPORTANT: The following section is required for all locations EXCEPT Penn State Health and the College of 
Medicine.  Penn State Health and College of Medicine should skip this section and complete “HRP-598 
Research Data Plan Review Form.” In order to avoid redundancy, for this section state “See the Research Data 
Plan Review Form” if you are conducting Penn State Health research. Delete all other sub-sections of section 
22.
See the Research Data Plan Review Form
Bibliography
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El-Bayoumy, K., et al., Carcinogenesis of the Oral Cavity: Environmental Causes and Potential Prevention by Black 
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Guttenplan, J.B., et al., Effects of Black Raspberry Extract and Protocatechuic Acid on Carcinogen-DNA Adducts and 
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