Relational Agents in Cervical Cancer Education (RACE)
Phase: NA
Conditions: Cervix Cancer, Human Papilloma Virus, Vaginal Cancer, Vulvar Cancer
Sponsor: Radhika Gogoi

Submission Date: [June 18, 2021] 
Protocol Version #: [3] 
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Relational Agents in Cervical Cancer Education (RACE): Phase II 
 
 
Principal Investigator 
Radhika Gogoi, MD., Ph.D. 
Associate Professor  
Karmanos Cancer Institute  
Wayne State University School of Medicine  
4100 John R: HP07G0 
Detroit, MI 48201 
313-576-9435 
Email: gogoir@karmanos.org 
 
Co-Investigators 
Thanh Bui, PhD 
Joan Walker, MD 
Timothy Bickmore Ph.D. 
J.J. Wallbilich MD  
Robert Morris MD 
Ira Winer MD, Ph.D.  
 
Statistician 
Seongho Kim, Ph.D. 
 
 
B. TITLE: ReIational agents in cervical cancer education: Phase II 
C. OBJECTIVE: 
Primary objective: To determine the feasibility of a relational agent based interactive 
intervention in educating cervical cancer patients about HPV and HPV vaccine implementation 
in their families and communities by measures of rate of participation and rate of completion of 
survey. 

Submission Date: [June 18, 2021] 
Protocol Version #: [3] 
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Secondary objective: To examine pre and post test measures separately by arm in 
exploratory analysis of: 
• Intention to discuss HPV vaccination with families 
• Health literacy 
• Behavior control, Social norms 
• Stigma 
D. BACKGROUND AND SIGNIFICANCE: 
According to the Centers for Disease Control and Prevention (CDC) in the United States, high- 
risk human papilloma virus (HPV) accounts for about 43,000 HPV-related cancers each year 
(CDC). HPV is the etiologic agent for 91% of all cervical, 70% of all oropharyngeal, 91% of anal 
cancers 1. Black and Hispanic women have higher rates of HPV associated cervical cancers than 
women of other races. While the rates of cervical cancer have continued to decrease by 1.6% 
per/year between 1999-2015, the rates of oropharyngeal cancers have increased by 2.8% per 
year among men and 0.6% per year among women. This increase is largely due to the increase 
in HPV related oro-pharyngeal cancers 2. The CDC estimates that 92 percent of all HPV 
associated cancers are attributable to the HPV types that are included in the HPV vaccine and 
could be prevented if HPV vaccine recommendations were followed. HPV vaccination is 
recommended in all adolescents starting at age 9-26. Since Oct 2018 the CDC has extended the 
recommended age for vaccination to age 45. We are far short of the Healthy People Goal of 
80% vaccination, with recent data reporting vaccination completion rates of 49% amongst 
adolescents between 13-17 years of age 3. 
We hypothesized that cervical cancer survivors armed with the correct tools could serve as 
community health educators and advocates for HPV vaccination within their social networks. 
Our preliminary data in a survey of cervical cancer survivors (unpublished survey data collected 
from Geisinger Health cervical cancer survivors by Larson et al), 82% reported that they had a 
conversation with family members about their cancer. Among those responding to the survey, 
about 66% reported a discussion about the kind of cancer, however only 36% reported having a 
conversation about the cause of their cancer, and 29% reported discussing an important 
prevention strategy, HPV vaccination. Among survey respondents who did discuss cancer with 
their family, 38% reported that they had not had a conversation with their doctor about the 
connection between HPV and cervical cancer. Moreover, among these same participants, 21% 
did not know about the Gardasil vaccine. Pt additionally identified embarrassment and fear of 
judgement (stigma) as reasons for not discussing their diagnosis with family members. 
Based on this gap in the data and the potential of therapeutic benefit, the proposed pilot 
project will explore effective strategies to educate survivors of an HPV related disease (cervical 
cancer) in a racially diverse urban cancer care setting. One promising strategy is the use of 
relational agents (RAs). RAs simulate face-to-face counseling sessions with health providers 
using speech and animated nonverbal behavior such as hand gestures and facial displays. In 
prior research conducted by Dr. Bickmore’s team, the RA has been shown to be an acceptable, 
user-friendly, highly accessible, and effective patient education and counseling system, 
especially with older adults, racially diverse populations and patients with limited health 
literacy.4-7 

Submission Date: [June 18, 2021] 
Protocol Version #: [3] 
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The proposed work is guided by the theory of planned behavior which suggests that one’s 
intention to engage in a behavior (i.e. discussing HPV vaccination) is directly influenced by ones 
attitude about the behavior (vaccine hesitancy, stigma), perceived subjective norms (what 
value their physician placed on HPV vaccination), behavioral control (their ability to discuss 
vaccination) and self-efficacy. These individual domains will be assessed on the HPV pre/post 
survey. 
 
E. ELIGIBILITY AND RECRUITMENT 
Inclusion Criteria: 
• Adults age 18 and older 
• Patients with an ICD9 diagnosis of cervical/vaginal/vulvar cancer or dysplasia 
receiving care at Karmanos Cancer Institute or OU Health Stephenson Cancer Center 
Exclusion Criteria: 
• Patients who are recorded in the EHR as requesting to be removed from research. 
• Non-English speakers. 
• Any cognitive disability that prevents informed consent 
• Any individual recruited in previous phases of the Study will be excluded. 
 
F. METHODS: 
Procedures: 

Submission Date: [June 18, 2021] 
Protocol Version #: [3] 
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Patients who are seeking care at the gynecologic oncology clinic at Karmanos Cancer Institute or the 
Stephenson Cancer Center with a diagnosis of cervical cancer will be identified. A waiver of consent to 
pre-screen potential eligible patients will be utilized to better identify these individuals. Research 
assistants will be trained by investigators to identify and approach potential participants in clinic. 
Potential participants will be approached by the RA’s and asked if they would like to hear more about the 
study. If the individual expresses interest, the RA will invite her to a private space on site and further 
describe the study, answer questions or concerns and obtain informed consent. Sixty cervical cancer 
patients, 30 from each site, will be enrolled into two arms (with-RA arm: 30 patients and without-RA 
arm: 30 patients). Patients in the RA arm will view a relational agent video on a tablet. The entire video 
will take approximately 15-20 minutes depending on patient level of engagement. Patients in the control 
group will receive a standardized handout on HPV and vaccine education which should similarly require 
10-15 minutes. All participants (standard and RA group) will complete the HPV Vaccine/Cervical Cancer 
Knowledge and Attitude Survey (see attachment, HPV Survey1 and 2) pre and post intervention. Surveys 
have been designed to assess demographics, HPV education, vaccine hesitancy, subjective norms, 
intention, behavioral control, attitude towards HPV vaccination, health literacy and stigma based on the 
theory of planned behavior as measures of our secondary objectives. Participants will receive a gift card 
for $5 for each survey at the end of their completion of both the pre and post surveys. Patients will be 
asked to allow us to send them a f/u survey (see attachment, HPV follow-up survey) via either a link by 
email or paper copy (with return envelope and stamp provided) by mail six weeks post-intervention to 
assess follow through. An additional $5 will be mailed to the participant upon receipt of the survey. After 
completing the follow-up survey, 20 participants (roughly 10 from each site) will have the potential to 
complete a final in-depth interview over the phone to provide further feedback. Interviews will be audio 
recorded for clarity and further analysis. Potential participants will be identified by the study personnel. 
Upon completion, participants will be mailed final $10 gift card. RA’s will be trained to observe and 
record issues related to feasibility, the informed consent process and clarity of survey which will be 
discussed by the study team. We anticipate approximately a 50% response to the follow-up survey. The 
initial survey questions given to the focus group follow a questionnaire previously devised and 
administered by Dr. Larson for an adolescent HPV vaccination and attitude survey. 
Risks and Benefits: Risks include potential emotional distress or discomfort from discussion of 
personal information, heath issues and cancer care. Research assistants will remind participants 
of the voluntary nature of the research and that participants have the right to not answer 
specific questions and may withdraw from the study at any time and for any reason. 
Measures (see Qualtrics survey block questions): 
• Demographics: age, race/ethnicity, income, family members, religious 
affiliation, education. 
• Social norms will be assessed with 4 items assessing cervical cancer related 
injunctive norms and descriptive norms. 
• Behavioral control- level of control and ease or difficulty in receiving HPV vaccine 
(vaccine hesitancy) 
• HPV knowledge 
• Health literacy 
• Stigma

Submission Date: [June 18, 2021] 
Protocol Version #: [3] 
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G. DATA MANAGEMENT AND CONFIDENTIALITY 
 
The current study will provide the same level of confidentiality as is standard with medical 
information. All participants will be assigned a numeric code so they cannot be identified in 
publications and presentations. While the specific participant will not be identified, pre, post 
and follow-up surveys from the same patient will be compared before and after the 
intervention. Patient permission will be requested to mail out surveys at 6 weeks to assess 
follow through with HPV vaccination discussion. Research records (electronic survey data) will 
be kept on a secure shared drive and be encrypted and password protected. Only the PI and 
the study team will have access to these records. The PI will secure an encrypted, password 
protected electronic cross-referenced file that will link numeric codes with participants 
consent forms. No investigational drugs will be administered, and no investigational devices 
will be used. 
 
H. STATISTICAL CONSIDERATION 
Objectives 
The primary objective is to determine the feasibility of a relational agent based interactive 
intervention in educating cervical cancer patients about HPV and HPV vaccine implementation 
in their families and communities by measures of rate of participation and rate of completion of 
survey. 
The secondary objectives are to examine the change from pre to post/follow-up intervention 
survey as exploratory analysis separately by arm: 
1. To examine the change in intention measures in pre and post intervention surveys and 
between pre and follow-up surveys separately by arm. 
2. To examine the health literacy of women with cervical/ vaginal cancer in regards to their 
knowledge of the HPV virus and prevention in pre and post intervention and follow-up surveys 
separately by arm. 
3. To examine the change in social norms and behavioral control measures in pre and post 
intervention surveys separately by arm. 
4. To examine change in stigma measures in pre and post intervention surveys separately by 
arm. 
Measurable variables 
The primary measurable variables of interest are the rate of participants and that of survey 
completion, which will be defined as the ratio of the number of participants to the number of 
patients who were asked to join the study and the ratio of the number of patients who 
complete the survey to the number of participants, respectively. The secondary measurable 
variables are changes from pre to post/follow-up intervention survey for (i) intention to discuss 
HPV vaccination with families, (ii) health literacy (such as HPV knowledge), (iii) behavior control 
and social norms, and (iv) stigma. The other measurable variables of interest are patient 
demographics (age, race, income, etc.). 

Submission Date: [June 18, 2021] 
Protocol Version #: [3] 
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Sample size and power justification 
The study has two parallel arms: with-RA arm and without-RA arm and the patients will be 
recruited for each arm simultaneously and using randomization. The without-RA arm is 
needed to estimate an effect size for the future main 
trial. The sample size was not formally justified and but 
decided based on several factors: resources and pilot 
two-arm study. In particular, we desire to have a 
medium effect size (0.5) for the future main trial with 
90% power at a 2-sided 5% level. Thus, according to 
Whitehead et al. (Statistical Methods in Medical 
Research, 2016; 25(3): 1057-1073), we plan to have 15 
patients per arm, yielding a total of 30 patients who 
will enter the study. The required number of eligible 
patients to be asked is estimated according to the 
expected rates of participants in order to accrual 30 
patients (= 15 patients x 2 arms) in Fig. 2. For example, 
if the expected participation rate is 0.5, 60 eligible 
patients should be asked to join the study in order to 
enroll 30 patients. 
Analysis 
Patient baseline characteristics will be summarized by count and percentage for categorical 
variables and median and range for continuous variables, separately by groups. The numbers of 
participants and survey completion will be summarized descriptively with count, percentage, 
and confidence interval, separately by arm (only for survey completion). The change of each of 
secondary endpoints will be summarized with mean, median, standard deviation, and 
confidence interval after, if needed, data transformation, separately by arm. In particular, the 
rate of survey completion will be calculated for each survey separately by arm. 
Expected accrual and study duration 
During a two-year period (across from 2015 to 2017), ~300 eligible patients were seen at Karmanos 
Cancer Institute (KCI) with either cervical dysplasia or cervical cancer (i.e., ~150 eligible patients per year 
with 4 gyn-oncologists). We conservatively estimate the accrual rate at KCI with 20% variation, yielding 
an expected number of at least 120 eligible patients per year (= ~150 patients per year x 80%). We also 
anticipate that the participation rate will be at least 50%, thus requiring 60 eligible patients to be asked 
for the study population of 30 patients. The expected accrual duration is therefore 8 months (= 60 
eligible patients x 12 months / 120 patients). Considering additional 6 months for IRB approval and data 
analysis, the expected study duration is 14 months. 

Submission Date: [June 18, 2021] 
Protocol Version #: [3] 
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STUDY SCHEMA: 
 
 
 
Screened 
Consent 
Intervention: 
Relational 
Intervention: 
Control 
Survey 3:  
Follow-up 
Survey 1:  
Baseline 
Survey 2:  
Post Survey 
In-Depth 
Interviews 
(20 participants)  

Submission Date: [June 18, 2021] 
Protocol Version #: [3] 
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7.0 REFERENCES 
1. https://www.cdc.gov/cancer/hpv/statistics/cases.htm. 
2. Van Dyne EA, Henley SJ, Saraiya M, Thomas CC, Markowitz LE, Benard VB. Trends in 
Human Papillomavirus-Associated Cancers - United States, 1999-2015. MMWR Morb Mortal 
Wkly Rep 2018;67:918-24. 
3. Tracy KA, Quillin JM, Wilson DB, et al. The impact of family history of breast cancer and 
cancer death on women's mammography practices and beliefs. Genet Med 2008;10:621-5. 
4. Bickmore TW, Pfeifer LM, Byron D, et al. Usability of Conversational Agents by Patients 
with Inadequate Health Literacy: Evidence from Two Clinical Trials. Journal of Health 
Communication 2010;15:197-210. 
5. Bickmore WT, Utami D, Matsuyama R, Paasche-Orlow KM. Improving Access to Online 
Health Information With Conversational Agents: A Randomized Controlled Experiment. J Med 
Internet Res 2016;18:e1. 
6. Sequeira SS, Eggermont LHP, Silliman RA, et al. Limited Health Literacy and Decline in 
Executive Function in Older Adults. Journal of Health Communication 2013;18:143-57. 
7. Bickmore T, Paasche-Orlow M, Aziz M, Barry B. Health Literacy and Usability of Clinical 
Trial Search Engines. Health Literacy Annual Research Conference 201

Submission Date: [June 18, 2021] 
Protocol Version #: [3] 
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