A Multilevel Gaming Intervention for Persons on PrEP
Phase: NA
Conditions: MSM, PrEP, HIV Risk
Sponsor: Rhode Island Hospital

A Multilevel Gaming Intervention for Persons on PrEP 
NCT02611362 
Latest Approval Date:7/12/2019

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Significance 
The primary prevention of HIV infection remains a crucial priority. In 2011, there were 2.5 million new 
HIV infections worldwide.(1) In the U.S., young minority men who have sex with men (MSM) are most likely to 
become infected with HIV and the use of antiretroviral medications to reduce the risk of acquiring HIV infection 
(Pre-exposure Prophylaxis, PrEP) is an efficacious and promising new prevention strategy.(1,2)  There have 
been recent significant advances regarding PrEP including the definitive demonstration that PrEP reduces HIV 
acquisition, the regulatory approval of Truvada (tenofovir/emtricitabine) with an indication for sexual HIV 
prevention, and the development of clinical prescribing guidelines. Despite these promising events, the 
practical implementation of PrEP is likely to be challenging.(3-10) Data shows that PrEP’s safety and 
effectiveness could be greatly compromised by suboptimal adherence to treatment and there is concern about 
the potential for an increase in HIV risk behavior among PrEP users.(11-15) Due to these challenges, the 
prescribing of PrEP should be accompanied by behavioral interventions. 
Adherence to medical care is an integral factor in PrEP’s effectiveness. The iPrEx, TDF2, and 
Partners PrEP clinical trials all conclusively showed that the level of protection from HIV infection depended on 
how consistently participants took prescribed medication. Significantly greater levels of protection occurred 
among participants with detectable levels of  antiretroviral medication (ARV) in all of these trials.(16,17,18) The 
impact of adherence was also underscored in the FEM-PrEP and VOICE studies, both of which found that few 
women had detectable levels of ARVs and the studies were unable to demonstrate the efficacy of 
PrEP.(15,19,20) Adherence to medication is critical to prevention with PrEP, however, engaging patients in 
comprehensive follow-up care is also imperative.(21) Treatment with PrEP will require consistent contact 
between patients and clinical providers and will include laboratory monitoring, HIV testing, the detection and 
treatment of associated side effects, and in cases of unsuccessful prevention, the treatment of newly acquired 
HIV infection.(5,10-15) Individuals who are at highest risk of HIV infection, often come from populations that 
historically have been underserved by healthcare.(23,24) Therefore, engaging patients in care could be 
challenging and will require reinforcement and support for doctors and patients.(13,23) Behavioral 
Interventions promoting adherence  to comprehensive PrEP treatment will need to be tailored to underserved 
and at risk populations and will need to reinforce the clinician-patient relationship. 
PrEP could lead to increased behavioral risk in real world settings. Although there is great 
optimism about the use of PrEP for HIV prevention, a concern is that PrEP users might take more sexual risks 
or decrease traditional risk reduction strategies such as condom use and HIV/STI testing of partners. 
Behavioral models (Behavioral Disinhibition and Risk Compensation) suggest that risk could increase by 
reduction of self-imposed constraints or by decreasing individuals perceptions of HIV risk. This, in turn, could 
lead to increased incidence of HIV and other STIs.(14,22,25,26,27) Some mathematical and cost effectiveness 
models have suggested that even small increases in risk behavior could offset or reverse PrEP’s protective 
benefits at the population level.(13,14) Little evidence is available regarding the actual impact of PREP on risk 
taking. Data from the iPREX study showed only indirect evidence of increased risk behaviors, as those 
participants who engaged in unprotected anal sex were more likely to have detectable tenofovir levels than 
those with less sexual risk taking.(17,28) In real world clinical settings, in which people know they are on an 
active medication, behavioral risk taking could measurably increase. Increases in risk behaviors have been 
documented in the context of microbicide trials, vaccine trials, and among patients living with HIV on 
antiretroviral therapy.(32) Therefore, HIV prevention counseling remains clinically relevant and prudent when 
prescribing PrEP. This practice is consistent with good clinical care and is recommended in interim guidelines 
for prescribing PrEP which state PrEP has the potential to contribute to effective and safe HIV prevention for 
MSM if  “it is delivered as part of a comprehensive set of prevention services, including risk-reduction and 
PrEP medication adherence counseling.”(138) 
The behavioral interventions accompanying PrEP need to be scalable, cost-effective, and easily 
integrated into clinical settings. In order to maximize the positive impact of PrEP, it is necessary to combine 
the prescription of PrEP with behavioral interventions that promote both adherence and the reduction of HIV 
risk behaviors (2). However, these accompanying behavioral interventions need to be cost effective and easily 
integrated into clinical settings in which PrEP is prescribed.(33) Additionally, interventions should be enjoyable 
and tailored to populations targeted for prevention with PrEP. Without these necessary components, 
integration of behavioral interventions into clinical settings cannot be realistically sustained. Although data on 
behavioral interventions accompanying PrEP treatment is limited, there is a comparatively large amount of 
information available on interventions that promote adherence and health behaviors in similar clinical 

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populations and settings. This data will be used to guide the development of our promising multilevel gaming 
intervention.  
 
Literature on adherence to antiretroviral treatment (ART) among persons living with HIV is 
available to inform behavioral interventions accompanying PrEP.  Studies have examined the effects of a 
variety of technological aids in improving adherence in adults such as handheld devices, two-way pagers, and 
alarmed medication vials.(46,54-61) However, these studies show that reminder devices and alarms, utilized 
without informational or motivational components, are only minimally effective in enhancing sustained 
adherence.(48,57,60,69) Devices that record pill cap opening events for patients and providers have been 
most useful for measuring but not improving adherence.(62,67,68) There is a strong correlation between pill 
bottle opening events measured by devices such as MEMS (or the electronic pill organizer proposed in this 
study) and virologic response to ARV. Therefore, pill cap opening monitoring technology has remained a gold 
standard in measuring medication adherence.(62-68) But, for the successful promotion of sustained adherence 
to ARVs, the underlying causes of non-adherence must be targeted such as poor information about HIV and its 
consequences, inconsistent motivation, and a lack of skills needed for healthy behaviors.(70-72,77) The most 
promising adherence interventions have investigated multi-component interventions that couple electronic 
reminders and/or pill bottle opening measurements with more costly in-person interventions to improve 
motivation for adherence behaviors.(48,62,76,78) Reviews suggest that the optimal technology enhanced ART 
adherence interventions: a) utilize tools that are easy to use, do not attract attention, are familiar, relevant, and 
tailored to the patient population (60,63,79,80); b) promote involvement with healthcare providers 
(69,73,81,75); c) incorporate strategies to increase information (e.g., HIV treatment knowledge and 
consequences of non-adherence), motivation (e.g., treatment benefits and concerns), and behavioral skills 
(e.g., methods for adherence).(46,63,69,71,73-75,79,81-83).  
 
The Information-Motivation-Behavioral Skills (IMB) model is a well-established 
conceptualization for improving adherence to treatment as well as decreasing HIV risk behaviors. HIV 
prevention and ART adherence interventions based on IMB have demonstrated efficacy(86-88) and reviews 
have suggested that interventions guided by accepted theories of change are more efficacious than those not 
driven by theory.(47) According to the IMB model, health information, motivation, and behavioral skills are the 
fundamental determinants of health behavior. In order for a PrEP-related intervention to be successful, the 
PrEP user must learn information that is directly relevant to PrEP adherence and HIV transmission. Knowledge 
is a necessary but not sufficient condition for change. Personal motivation to engage in HIV preventative 
behavior or adhere to treatment regimens (attitudes about health) and social motivation (perceived social and 
cultural support for performing these acts), is essential for change. Finally, skills for performing adherence 
behaviors and a sense of self-efficacy must be easily applied to an individual’s cultural and social setting. A 
most recent review of factors associated with PrEP adherence suggests that adherence can be facilitated by 
“accurate knowledge of medication benefits”, “medication optimism and self efficacy for adherence,” and 
“support provided by peers and providers.”(29). Our intervention will address these factors within the context of 
the IMB model. This model, consistent with Social Learning Theory, is broadly applicable and can be used to 
create theoretically consistent intervention content.(89) 
 
Utilizing gaming technology to deliver behavioral interventions for MSM has many advantages. 
Most technology-based interventions that aim to improve intrinsic motivation, information, and build behavioral 
skills for adherence have involved in-person engagement in combination with a variety of reminder or event 
recording technologies. However, there are many advantages to using newer interactive technology to improve 
motivation and skills, rather than traditional face-to-face counseling, including scalability, efficiency and cost 
effectiveness. In this project, we will leverage technology, not to just remind and sensitively record adherence 
behaviors, but to also to engage patients in learning information, practicing behaviors and improving motivation 
for safe sexual behaviors and increased adherence to PrEP. The use of a combination intervention that utilizes 
gaming technology is particularly compelling for use with younger adults, as this age group is most at risk for 
acquiring HIV and this age group has most actively inquired about PrEP in our clinical settings. Young male 
adults in the United States, spend on average 1.13 hours per day playing interactive computer and video 
games. According to the Pew Internet and American Life Report, Adults and Video Games, 53% of all 
American adults play video games and 81% of all younger adults 18-29 years old play video games. Fifty 
percent of these young adults state they play ‘everyday’ or ‘a few times a week’(90). Gaming technology is also 
popular among minority MSM, the sub-group most at risk for acquiring HIV. In the past, gaming was mistakenly 
identified as a primarily adolescent and heterosexually dominated activity, but current data supports that 
gaming is actually quite diverse.(90) MSM gamers, referred to as “gaymers” in pop-culture and main stream 

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articles, are highly represented online and increasingly shape the market (34,35,36,38). Additionally, within the 
United States, African Americans ages 18-35 yrs old represent the most active and fastest growing user group 
of the mobile Internet (37,39) and more than half of reported video gaming occurs on portable devices.(90,37) 
Furthermore, MSM have been shown to have greater access to and use of cell phone technologies compared 
to heterosexual populations(38) and mobile phone teledensity (i.e. number of phones per person) has reached 
above 90% in most developed countries. The widespread appeal and use of smart phones and video game 
playing creates a unique opportunity to deliver health education to MSM on PrEP, during leisure time, outside 
of the clinic, in a manner that is cost effective and easily scalable.(41,84,85,91)  
Interactive game play has been shown to enhance players' motivation to improve health 
behaviors and self-care in a variety of clinical settings and populations. Games can attract and maintain 
attention; a key component for effective behavior change. Compelling interactive phone based games can 
expose players to essential health related content thousands of times and also give players unlimited 
opportunities to rehearse new skills and receive personalized feedback on health choices made within the 
game. (92-94) Games have been shown to be efficacious in promoting fitness, improving weight management, 
and improving safer sex skills.(91,92,94,100) For example, a HIV/AIDS-prevention computer game called Life 
Challenge was developed by the New York State Department of Health to enhance safer sex negotiation by 
adolescents and young adults. The game showed significant improvement in self-efficacy for partner 
negotiation and condom skills for those who started with the least self-efficacy.(94)  Two pregnancy prevention 
games, The Baby Game and Romance, designed for sexually active young adults, showed trends in improving 
knowledge and attitudes about parenting and unprotected sexual behaviors.(93) 
Video games have also been applied to improve self-management skills and healthy behaviors in those 
living with asthma, diabetes, and cancer.(95-99) For example, a diabetes game called Packy and Marlon, 
demonstrates that  a well-designed, educational video game can be effective in improving diabetes-related 
self-efficacy (p = 0.07), communication with clinicians and loved ones about diabetes (p = 0.025), and self-care 
behaviors (p = 0.003). These changes occurred after the game was played at home for six months, compared 
to no improvement in diabetes-related outcomes in a control group who took home an entertainment video 
game that had no health content.(96) In a game called Bronkie the Bronchiasaurus, those with asthma help a 
dinosaur character avoid asthma triggers (pollen, cold viruses, dust) and keep his asthma under control. An 
empirical study showed that playing the game for less than an hour resulted in significant improvements in a 
player’s asthma knowledge, self-efficacy for asthma self-management, and self-efficacy for talking with 
supports about asthma.(95,97) Another video game, named Re-Mission, designed for a wide age range of 
patients (13-29 yrs) with acute leukemia, lymphoma, and soft-tissue sarcoma, showed promising effects as 
well. Re-Mission was designed as an action–adventure game with the main character or protagonist shooting 
cancer-causing agents in the bloodstream. Players gain points and strength by adhering to medications in the 
game fantasy world.  In a randomized control study with a three month follow up, 375 male and female 
participants who played Re-Mission had significantly improved adherence to trimethoprim-sulfamethoxazole 
(p=.012) and 6-mercaptopurine (p=.002) compared to controls after an average of only 10.7 hours of play. 
Adherence to TMP/SMX was tracked by electronic pill-monitoring devices (n=200) and the proportion of doses 
taken correctly by those playing Re-Mission was 19% greater than those in the control group.  Self-efficacy 
(p=.011) and knowledge (p=.035) also increased significantly compared with the control group. Interestingly, 
the intervention did not affect subjective self-report measures of adherence but did effect the above objective 
measure.(98,99) Thus, appealing interactive games can target information, motivation and skills for medical 
care and have led to a broad spectrum of desirable outcomes including increases in knowledge, attitude 
changes, and increased medication adherence.(91,100,102-104) 
The video games most successful in influencing behavior have common traits. Games that 
utilized a theory of behavior change (with behavior-change concepts inserted in the game play) and involved 
the use of story and fantasy were effective.(93-103) The successful games reviewed above provided simulated 
interactive environments where players engaged in behavioral rehearsal.(101-102) The simulated 
environments of the games served as a safe place to practice self-management skills. Players could observe 
detrimental effects of their own mismanagement of a disease without engaging in real danger. These findings 
support current efforts to develop effective video-game interventions for education and training in health care. 
Innovation 
The use of antiretroviral medications to reduce the risk of acquiring HIV infection (Pre-exposure 
Prophylaxis, PrEP) is a promising new prevention strategy. Optimal PrEP treatment will require simultaneous 

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medical care and monitoring as well as behavioral interventions to promote adherence and safer sexual 
behaviors. In order for interventions to be most successful they must be targeted to populations most at risk. 
There are many advantages to using newer interactive technology, rather than traditional face-to-face 
counseling, including scalability, efficiency, cost effectiveness, and appeal. In this project, we will leverage 
technology, not to just record adherence behaviors, but to also engage patients in learning skills, practicing 
behaviors and improving motivation for adherence and healthy behaviors. We are not aware of any PrEP 
related intervention that integrates medication monitoring technology with a theoretically informed game that 
enhances information, motivation, and behavioral skills for PrEP adherence. An intervention with these 
components may empower and engage PrEP users, aid over-burdened clinics, and result in improvements in 
health.  
Approach 
Preliminary Studies 
Our research team is composed of experts in biobehavioral HIV prevention and care, gaming to promote 
adherence, and we have one of the few PrEP implementation clinics in the country.  We are poised to become 
experts in the clinical use of PrEP in the U.S. Our diverse team will inform this developmental study with a pilot 
RCT. The project will result in the development of a cutting edge, engaging, and entertaining app/game that 
successfully achieves improvements in adherence to PrEP as well as improvements in HIV prevention 
knowledge, skills, and behavior. 
Expertise in HIV Prevention, Biomedical Research, and Technology for Behavioral Change.  Dr. 
Whiteley and Dr. Brown are both psychiatrists with clinical and academic expertise HIV prevention, adherence, 
and gaming for behavior change.  Dr. Whiteley has a research focus on the applicability of new technology for 
promoting health and adherence. Dr. Phillip Chan, Director of the PrEP clinic at Rhode Island Hospital, is an 
infectious disease doctor and researcher who specializes in HIV care and prevention. Dr. Michelle Lally is also 
an infectious disease physician with experience in HIV care and HIV biomedical research (including PrEP 
related research) as an investigator in the NIH Adolescent Medicine Trials Network for HIV/AIDS Interventions 
(ATN) and the HIV Vaccine Trials Network (HVTN) (141). She is Director of the Brown University AIDS 
Program (BRUNAP), and co-Director (with Dr. Brown) of the Prevention Sciences Core of the 
Lifespan/Tufts/Brown Center for AIDS Research.  
 Dr. Whiteley has done preparatory qualitative and quantitative work regarding PrEP and has focused on 
the use of newer technologies and HIV related health behaviors. (111,112, 113) She is the PI on a recent 
Center for AIDS Research (CFAR) developmental study in which 60 African American young adults at high risk 
for acquiring HIV (18-24 yrs old) were given an online intervention that included gaming modules and 
informational modules on PrEP. Quantitative data determined that interest in PrEP was greatest among those 
with a history of anal sex (OR = 8.4, p<.05), even when controlling for condom use at last sex in a multiple 
logistic regression. As part of this study, Dr. Whiteley also conducted qualitative interviews about knowledge 
and attitudes towards PrEP with 25 predominately African American (79%) young adults identifying as MSM 
(18-24 yrs old).(139)  Most participants (75%) interviewed were very interested in starting PrEP. Concerns 
about PrEP included: that sexual risk could increase “cause people won’t worry about what they could get,” 
and participants stated they would be “unlikely to take PrEP if I am with my main person,” participants also 
stated, “why bother using condoms, if this pill can be so protective?” Also cultural themes emerged: “we worry 
that White doctors actually want us to get HIV.” These data reinforce that young adults at behavioral risk for 
HIV, especially those engaging in anal sex, are interested in PrEP, and are concerned about issues of 
adherence, risk compensation, and healthcare provider motivations. 
Drs. Brown and Whiteley are also PI and CO-I respectively on an iPhone gaming intervention to improve 
adherence to antiretroviral treatment in young adults living with HIV (90% MSM, mean age 24 years) [R01 
HD074846]. This game focuses on medication adherence and sexual risk reduction in those already living with 
HIV. Dr. Whiteley and Brown have worked extensively with the gaming company that we will use in this project  
(Mission Critical Studios-MCS, see below) and Dr. Whiteley was able to develop and refine her idea of linking 
smart technology on pill dispensers with smartphone games with MCS. This technology and iPhone game 
have been evaluated by 23 predominately African American participants (20 MSM, mean age 24, 70% 
Black/African American) living with HIV and all participants have had a very positive response to the gaming 
graphics and Wisepill linkage. Sixteen of the 20 MSM played the game to completion and average game play 
measured approximately 10 hours per week (as measured by gaming software). MSM participants rated the 
game very highly (mean item scores of 3.7 on the Client Satisfaction Questionaire and 3.6 on the Session 
Evaluation Form). Both measures are 4 point Likert items with higher numbers indicating more satisfaction 

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(See Approach: Open Trial/ Quantitative Assessment and Appendix).(140) Our past gaming and technology 
experience greatly facilitates the development of this proposed project and similar, detailed quantitative and 
qualitative work will ensure the same level of acceptability for minority MSM participants on PrEP. 
 
Dr. Brown has also tailored HIV prevention interventions in four NIH-funded RO1 RCTs. All of these 
tailored interventions have reduced sexual risk and have focused on risk perception, decision making, and 
assertive prevention skills to reduce HIV risk.(105-109) One intervention outcome paper, with an impact lasting 
for up to 9 months, received the Reiger Award for Scientific Achievement from the American Academy of Child 
and Adolescent Psychiatry.(137) This expertise in HIV prevention and the tailoring of prevention programs for 
high risk populations is highly relevant for this project. Dr. Brown is also PI on two AIDS Trial Network (ATN) 
protocols that have adapted efficacious, theoretically informed interventions for young adults living with HIV.  
ATN Protocol 080 delivers tailored cognitive behavioral therapy (CBT) and evidenced-based medication 
management to treat Depressive Disorders and non-adherence to ART. ATN 069 delivered a tailored CBT and 
contingency management intervention to treat substance use as well as non-adherence.(42)  
Dr. Lally has expertise in the areas of biomedical HIV prevention. She is the Director of HIV Vaccine 
Clinical Trials at Brown/Lifespan, Director of the Brown University AIDS Program (BRUNAP), and Medical 
Director of the Rhode Island Clinical Research Center at Lifespan/Brown. She is also an advisory board and 
faculty member of the STD/HIV Prevention Training Center of New England. She is an investigator in the HIV 
Vaccine Trials Network (HVTN) and was an investigator on a PrEP study in the NIH Adolescent Medicine 
Trials Network for HIV/AIDS Interventions (ATN) entitled ATN 082: Acceptability and Feasibility of a Pre-
exposure Prophylaxis (PrEP) Trial with Young Men Who Have Sex with Men.  This study found that a PrEP 
placebo controlled trial with a behavioral intervention was acceptable to YMSM, however, only 63% of those 
taking PrEP had detectable tenofovir at study week 4 and only 20% by week 24.(141). Dr. Phillip Chan is the 
director of the HIV/STD Testing and Prevention Service at The Miriam Hospital Immunology Center. He is also 
the director of one of the first PrEP implementation projects in the country (in Jackson, MS and in Providence 
RI) funded by Gilead (Chan PI), see Setting in Approach. Dr. Chan’s research focuses on HIV transmission 
networks and incorporates molecular genetics, behavioral sciences, and clinical medicine.  
Dr. Jeffrey Fisher is the co-developer if the IMB model and an expert in IMB guided interventions. He has 
published extensively on factors associated with adherence and has done conceptual and empirical work in 
increasing HIV preventive behavior utilizing IMB theory. Dr. Fisher has designed and evaluated effective HIV 
prevention interventions in multiple populations. Dr. Fisher's research on HIV to date has involved MSM, 
injection drug users, heterosexual adolescents, and individuals who are HIV infected. He has been awarded 9 
major HIV risk reduction grants from NIH since 1989. He has lectured and consulted internationally. He will be 
consulting regarding the use of IMB framework for the gaming intervention.(142-145) 
Expertise in Gaming Technology. Game development will be done by Mission Critical Studios (MCS). 
They have extensive experience in developing games for implementation on PC, Mac, Apple iOS, Android, 
iPhone and all major Internet browsers. Mission Critical Studios has received high acclaim for their own 
gaming projects including Dr. Nano - 3D Artery Adventure, Dr. Nano X: Incredible Voyage Inside The Body, 
and Frantic Freddy Bug Stomp.  Mission Critical Studios has contracted and partnered with the following 
companies: Unilever, IBM, Hamon, Bank of America, SNK/Neogeo, and IBM. This company has also had an 
enjoyable and highly successful partnership with our research team in developing a gaming intervention for 
RO1 HD074846. Company skills include 3D Modeling, audio mixing, motion graphics, mocap cleanup, C#, 
JavaScript, Unreal Scripting, game design, animating characters, Photoshop cleanup and texturing, and UV 
mapping (by hand through Maya or automated through Zbrush). Company tools include Lightwave, 3D Max, 
MotionBuilder, Photoshop, After Effects, Flash, Unity, and UDK. Platform experience includes Windows PC, 
Mac OS X, and Cell Phone/WAP. Mission Critical Studios is a licensed developer for Microsoft Xbox, Nintendo 
Wii, Nintendo Wii Ware and Nintendo DS. The IMB Adherence Game to be developed for this project is 
preliminarily titled Viral Combat (See Appendix 1, pp. 2-17, for a storyboard and screen shots of the preliminary 
IMB adherence app/game). Viral Combat will be adapted and refined from the popular Mission Critical Studios 
game Dr. Nano X: Incredible Voyage Inside The Body. Beginning with this existing game allows the 
project to be done in a cost effective and efficient manner. Please see: 
http://www.youtube.com/watch?v=lyHzSZFzU1Q, www.missioncriticalstudios.com.  
Pill dispenser monitoring device. Compliance Meds Technologies, LLC. is the developer of the smart 
medication dispenser that we will be using. The CleverCap is a tamper-proof smart cap that fits onto a 
standard pill bottle. The CleverCap device can monitor, measure, and securely relay pill-by-pill or dose-by dose 
adherence behavior. The capability to record and analyze pill opening events is similar to MEMS. However, the 

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CleverCap device can be programmed to integrate into an array of wireless technologies and other web 
application interfaces. Each time a person opens their CleverCap, it wirelessly relays the data to CleverCap’s 
HIPAA-compliant secure network. Adherence reminders are integrated through visual and auditory alerts. The 
CleverCap generates a CleverScore that can be used as a measure of the actual utilization of medications 
versus the prescribed dosage over time. This instantaneous wireless capability differs from the traditional 
MEMS cap. Currently, the MEMS cap requires a MEMS reader linked to an office computer in a doctor’s office 
to update and collate bottle openings at weekly, monthly or other scheduled intervals. The wireless network 
infrastructure of the CleverCap device allows for timely applications to be instantly linked to their product. 
Compliance Meds Technologies, LLC was named the winner of the 2013 North America Frost & Sullivan for 
New Product Innovation Award.  
 
Design 
This research will be divided into two major phases: (1) a Development Phase (n=40) in which we will 
conduct formative research to guide the development of the gaming intervention and gain experience with its 
implementation in an open trial and (2) a small, pilot Randomized Controlled Trial Phase (n=50) in which we 
will evaluate the acceptability and preliminary efficacy of the IMB gaming intervention compared to a 
comparison condition. (A project activities timeline is in the Budget Justification section).  
Sample.  All MSM on PrEP over the age of 18 yrs old, will be eligible for enrollment in each phase of study 
according to the following criteria: 1) English speaking, 2) receiving prophylactic antiretroviral treatment 
(PrEP), 3) not enrolled in another PrEP related study, and 4) able to give consent/assent and not impaired by 
cognitive or medical limitations as per clinical assessment.  There will not be overlap between subjects in the 
Development and Controlled Trial Phase. We are enrolling only MSM because they are the group most at risk 
for acquiring HIV. Limiting the study to MSM will allow for the development of an iPhone app/game that is 
targeted, acceptable, and engaging for this specific at risk population. Based on data below, it is estimated 
that 65% of participants will be Black/African American, 30% will be Hispanic and the mean age will be 27. 
Setting. We will recruit participants from the PrEP Clinic directed by our co-investigator, Dr. Chan. This 
clinic receives the majority of its referrals from the HIV/STI Testing Clinic at Miriam Hospital, which is also 
directed by Dr. Chan. More than 500 new patients were seen in HIV/STI Testing and Prevention Clinic in the 
past year. Those at risk are counseled about and offered PrEP. Approximately, 5-8 people have been started 
on PrEP each month for the past 6 months (average of 7/month). Of those started on PrEP in the past year, 
85% were male, all had a significant HIV sexual risk history including recent unprotected anal intercourse with 
a male partner, recent anal sex with an HIV infected male partner, or multiple male partners in the past 3 
months with unknown HIV status. Sixty-eight percent had a history of a STI in the past year. The age of the 
men on PrEP ranged from 19-48 years old, with a mean age of 27 years (75% between ages18-30). Racially, 
65% of the patients identified as Black/African American and ethnically, 30% identified as Hispanic.  During 
the Qualitative Interview phase we will recruit 10 participants from the PrEP Clinic at the University of 
Mississippi Medical Center in Jackson, MS. These interviews will help us to develop a game that is widely 
acceptable to young MSM.   
Recruitment and retention. We will recruit 90 participants (40 in developmental phase and 50 in the RCT 
phase) over 2 recruitment periods, totaling 24 months. Conservatively estimating 6 new patients enrolled on 
PrEP each month and over 100 existing PrEP patients at the start of this study, we will be recruiting from a 
pool of 244 subjects, 85% of whom will meet eligibility criteria (207 at-risk MSM, 18yrs and older). Therefore 
we will only need to recruit 43% of the eligible sample. Our hospital has a long history of recruitment and 
engagement of adult and young patients with HIV for longitudinal and clinical treatment studies.(102,45) We 
have close ties with Miriam clinics and successful current collaborations with Drs. Chan and Lally. We were 
able to recruit >80% of eligible HIV infected subjects for our current gaming study (R01 HD074846) and the 
majority were younger MSM. Rhode Island’s small size and few HIV treatment resources both aid in the 
retention of clinical samples. Previous ACTG trials in the Miriam clinic have retained more than 85% of enrolled 
patients after more than six months and we estimate similar retention rates. Retention techniques for the study 
include maintaining updated participant contact information, frequent reminder cards, phone calls and emails, 
keeping records of friendship contacts, and obtaining the name and telephone number of another relative or 
family friend who would know of the patient’s whereabouts. The retention rate in Dr. Brown’s previous 
community study (U01 MH066785) was 92% after 18 months. The retention rate in Dr. Whiteley’s CFAR study 
with young adults at risk for HIV was 90%. 
 

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Development Phase  
The goal of the development phase (n=40) is to develop and refine the game (Viral Combat, Appendix 1, 
pp.2-17) for the intervention. This phase will establish acceptability and feasibility by participants of the gaming 
intervention. These steps will be accomplished by preliminary work by the scientific investigators in 
collaboration with Mission Critical Studios using data from qualitative interviews with 20 subjects (see Appendix 
2, pp. 43-47) and a small open trial that also includes qualitative interviews with 20 additional subjects. Multiple 
reviews have demonstrated that behavioral interventions shown to be most efficacious are tailored for the 
target population, and preceded by formative research to inform intervention development.(116-118) 
Game development will be accomplished using iterative and collaborative procedures to fully integrate the 
experiences of participants on PrEP.  As discussed in the Significance section, the app/game, Viral Combat, 
will be consistent with the IMB Model of Health.(66) The game will promote increased self-efficacy for 
adherence and HIV preventative behaviors by improving motivation, increasing mastery, improving information 
about health and prevention. Successful games are intuitive, engaging and inherently rewarding through action 
and feedback. Thus, many of the attributes of a successful game are a natural fit for a successful IMB-informed 
intervention. Screen shots for our initial draft game are included in Appendix 1, pp. 2-17.  
Initial development of the IMB Gaming Intervention. A preliminary story board for the IMB app/game 
proposed, Viral Combat, is currently drafted (Appendix 1, pp. 2-17). Viral Combat will be adapted and refined 
from the popular Mission Critical Studios game entitled Dr. Nano X: Incredible Voyage Inside the Body (see 
YouTube video- http://www.youtube.com/watch?v=lyHzSZFzU1Q , also see app store- 
http://itunes.apple.com/us/app/dr.-nano-x-incredible-voyage/id398001397?mt=8). This is a five star rated game 
in the iTunes app store and is available on both Android and iPhone. We have experience creating a game 
with MCS and tailoring it for predominately African American young adults living with HIV (See Preliminary 
Studies) and this past experience informs our protocol for the development process (See Appendix 1, 
Mission Critical Dev. Plan, pp. 18-28).  
The proposed game in this application (Viral Combat) differs significantly from the game previously 
developed for young adults living with HIV (R01 HD 074846). Participants playing the Viral Combat will be 
fighting virus before it infects and enters the body. The game will take place on the surface of the skin, in the 
arterial system, in the penile and anal canals (rather than in the brain, liver, kidneys as developed for the R01 
HD074846). HIV related educational material and games will be tailored to prevent HIV (i.e. importance of 
testing and using condoms), and not tailored to persons living with HIV (i.e. how viral load affects transmission 
and health). Adherence messages will be relevant to participants using PrEP for HIV prevention (i.e. taking 
PrEP doses as prescribed corresponds to level of protection) rather than for persons living with HIV (i.e. ARV 
adherence impacts viral mutations, CD4 counts, opportunistic infections). Similarities include software for 
motion controls, touch screen capabilities, integration with electronic pill dispenser, and tracking game usage. 
These similarities allow for the development of an iPhone app that is unique but within the proposed budget. 
Viral Combat storyboard (See Appendix 1, pp. 2-17). The IMB game/app, Viral Combat, will employ 
graphics, characters, action content specifically chosen to be appealing to our target population. Viral Combat 
takes place inside the human body and starts with a narrator, in a deep and dramatic voice, explaining the 
storyline and objectives of the game. The player is told by the narrator, “you have been chosen to be cloned. 
Your clone will be shrunk by the groundbreaking nano shrinking machine and turned into a nanobot!  As a 
nanobot, you will enter your own body to destroy attacking viruses that are trying to gain entry.” The narrator 
accompanies the player through the shrinking process. The narrator explains to each player “you will need 
weapons and tools to successfully destroy virus attempting to enter your body. You will earn protective gear, 
character enhancements and weapons by picking up pills, taking medication and building alliances with 
doctors and clinicians.” Players can skip this narrative, if they prefer, after the first time gaming. At the start of 
play, participants can also choose and design their individual, colorful nanobot characters with skin tones that 
can be customized. The first level begins on the skin’s surface. If players successfully battle virus, engage with 
providers, take medication, and make healthy decisions, they move to the next exciting level - the penis. 
During each mission, the player’s score (health status and adherence pill count) is shown. As players become 
expert nanobots, they move through the arterial system, and other body systems such as the anal canal and 
the mouth. All organ systems are vibrant and distinctive. Answering questions from the doctor/clinician, and 
building adherence and HIV prevention knowledge, allows each player to earn strength and points throughout 
Viral Combat. During play, if an answer to a question or skill building exercise is wrong, the player is alerted, 
and the correct answer is explained (See Appendix 1, p.10). “Health Facts” will reinforce HIV prevention 
information during scene changes. HIV prevention skills will be built with a condom “puzzle” and the “condom 

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use challenge” that promotes continued condom use with all partners and models assertive safer sex 
discussions (See Appendix 1, p. 14) If a participant misses a dose, the CleverCap software will send a game 
graphic and message to the participant’s phone. Each level in Viral Combat provides new challenges and 
unique and colorful environments, however, the mission stays the same: kill virus and build strength through 
taking medicine, learning HIV prevention information, improving motivation, and engaging with healthy 
charcters in order to build skills. All character control and gaming is done by cutting edge touch screen 
technology on the phone, no additional accessories are needed for play. Throughout the game the terms “HIV,” 
“AIDS,” “antiretroviral” and other identifying verbiage is avoided to protect the players’ medical status and to 
avoid possible stigmatization that could occur from someone seeing a participant playing the game (see 
Appendix 1, p.10). During the development stage we will also illicit feedback from participants regarding this 
issue and about the title. Necessary changes will be made if participants feel the game content or title is 
revealing, insensitive or stigmatizing.  
At the beginning of the project, all investigators and the collaborators will review the above elements of the 
proposed game and suggest modifications to improve its appeal, understandability, utility, and enjoyment by 
participants. We will also be assessing its consistency with the IMB Model. Modifications will be made by 
Mission Critical Studios. The process of development and initial adaptation will be done in the first 3 months of 
the project.  
Individual qualitative interviews (months 3-9). Initial detailed, in depth, structured, audiotaped individual 
interviews about the utility and appeal of the preliminary IMB Gaming Intervention, electronic dispenser, and 
study procedures will occur with MSM participants (est. mean age 27) receiving PrEP (See sample and setting) 
during months 4-9. The interviews will ensure that the assembled intervention is relevant to our target 
population. (116,117,119). We will perform interviews on a sufficient number of each relevant sub-group (Black 
vs. non-Black, older vs. younger than 25 yrs) until there is redundancy in themes and general feedback. All 
interviews will focus on how sexual orientation, race, stigma, culture, and age influence information, motivation 
and behavioral skills for the major targets of the gaming intervention (PrEP adherence, medical care 
adherence, and HIV prevention behaviors). Participants will give general reactions to intervention content and 
we will also look for deeper, or more complex, emerging themes to guide game graphics, content, and 
messages. For example, participants will be asked “As a black, gay male, how worried are you about getting 
HIV? How effective do you think PrEP is at preventing someone from getting HIV.” After viewing a preliminary 
storyboard or game, participants can be asked, “Which parts of the storyboard/game would influence how 
concerned you are about HIV?” “Which parts of the game increase your knowledge about how protective PrEP 
is?” “Could these messages be made more relevant to you and your friends, partners?” Participants will also 
be queried about the acceptability and relevance of game actions and graphics as they relate to race and 
culture. As currently proposed in our storyboard, players will be able to personalize their characters so that the 
game feels racially, culturally and personally relevant. Interviews will aid in determining the scope and design 
of this personalization. If characters are needed with darker or lighter skin, or more or less colorful clothing is 
needed, this variability can be added to game options.  
Drs. Brown and Whiteley have used qualitative and formative work to adapt interventions for persons at 
risk for HIV, those living with HIV, and minority MSM. For example, Dr. Brown and collaborators designed, with 
extensive qualitative work, a culturally tailored STI/HIV prevention campaign for African American teens with a 
TV/radio media component (119, 120), and Dr. Whiteley also designed, with qualitative work, a culturally 
tailored Internet based STI/HIV Intervention for African American young adults and MSM (See Preliminary 
Studies). Drs. Whiteley and Brown will conduct all interviews and code major topic and subtopics from the 
interviews and review findings with the investigators and collaborators as themes emerge.  
Revision to the IMB game (months 9-11): Drs. Whiteley, Brown, and Fisher will assess the intervention’s 
suitability for participants receiving PrEP, and its ability to improve adherence with material and techniques 
consistent with the IMB model. The team will assess the strengths and weaknesses of intervention 
components and indicate revisions to the preliminary IMB Gaming Intervention. We will also put all written 
content through a reader program to ensure that the reading level is appropriate. Mission Critical Studios will 
implement the changes using our iterative development process (see MCS Development Plan, Appendix pp. 
18-28).The investigators will review protocols and technological revisions for consistency, and potential 
technological problems.  
Open Trial: Qualitative and quantitative assessment of the gaming intervention (months 12-18).  A 
12 week open trial of the IMB Gaming Intervention, with individual qualitative exit interviews, will be conducted 
with 20 new participants on PrEP during the first half of year 2. The preliminary intervention will be tested in 

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order to refine the protocol, IMB app/game, electronic pill dispenser, and any other technological requirements.  
Procedures: After assessment and consent, each participant will receive ONLY a CleverCap electronic pill 
dispenser and instruction on its use. After one month of using the CleverCap dispenser only, participants will 
return for assessment. This intervening month will provide a period of time for participants to get oriented to the 
CleverCap dispenser, and it will also provide investigators with baseline measures of adherence without the 
IMB app/game. At this one month assessment participants will also be introduced and oriented to the 
adherence intervention game (Viral Combat) and the smartphone. The basic elements of the game will be 
demonstrated and the participants will have an opportunity to practice the game, with study staff, in order to 
build interest. Participants will be shown that each pill taking event, recorded by the CleverCap device, will 
trigger a game graphic text (e.g. missed doses will receive encouraging messages). Participants will 
demonstrate that they can operate the smartphone, game, and CleverCap dispenser. They will also be given 
contact information for technical assistance or protocol questions if needed prior to the 12 week study visit. 
Participants can receive technical assistance from trained RAs, Dr. Whiteley, and the technical staff at Mission 
Critical Studios.   
 
Quantitative Assessment: Participant’s overall satisfaction with the preliminary IMB Gaming Intervention 
will be surveyed using a modified version of the Client Satisfaction Questionnaire (CSQ-8) at the 12 week 
assessment. The CSQ is an 8-item measure with good reliability and validity. They will also complete a 
modified Session Evaluation Form (SEF), which has 13 items that reflect areas of feasibility and perceived 
utility of the intervention. Responses to items on these questionnaires will help determine the initial feasibility 
and acceptability. Subjects will also complete measures of HIV-related knowledge, attitudes and behaviors at 
baseline and at 12 weeks during this open trial (See Appendix 2, pp. 29-42). These measures are described 
below in the RCT phase as well. Mission Critical Studios can collect generalized, non participant linked, data 
on game usage through TestFlight software integrated into the game. This data shows the amount of time 
players spend on the game, percentage of times players complete levels, levels in which players spend more 
or less game time, etc. 
Qualitative Assessment: Drs. Whiteley, Brown, and staff will again use the structured individual qualitative 
interviews at the 12 week assessment to evaluate participants’ opinions on the goals of the gaming 
intervention, the clinical utility and relevance of the game, its strengths and weakness, its ease of use and 
barriers to use, and the ability of the study measures to capture their experience (See Appendix 2, pp. 43-52 
for preliminary structured interview guide, CSQ and SEF). There will be an emphasis on examining participant 
feedback for racial, cultural, or sexual specific trends in order to further tailor intervention content. The 
investigators will use all data to assess feasibility and acceptability of the intervention and make changes as 
needed. Based on these data, Viral Combat, will be modified by Mission Critical Studios during month 19-20 
using our iterative development process (see MCS Development Plan, Appendix pp. 18-28). The game and 
intervention procedures will again be reviewed and revised by investigators to create a final version of the IMB 
Gaming Intervention for the RCT. 
 
Randomized Controlled Trial Phase 
During months 21 to 33, we will evaluate the preliminary impact of the IMB Intervention (IMB app/game + 
CleverCap dispenser), compared to a comparison group- COMP (iPhone with non-IMB game + CleverCap 
dispenser) in a Randomized Controlled Trial with 50 participants on PrEP (eligibility criteria above, see 
Sample). Smartphones will be available to participants in the IMB Gaming Intervention and in COMP for the 
entire 24 week study period. The COMP participants will be given smartphones and a non-PrEP comparison 
game (also designed by Mission Critical Studios, see below) to control for attention, time, and any influence the 
receipt of a smartphone or game has on adherence behaviors or the physician-patient relationship. CleverCap 
dispensers in both conditions will record adherence. Our primary outcome will be the CleverCap openings 
measured daily for 6 months.  Secondary outcomes such as self report of medication adherence and sexual 
risk, HIV related knowledge and attitudes, clinical records (appointments kept, STI treatment), and ARV levels 
(tenofovir diphosphate, TFV-DP and Emtricitabine, FTC-TP) will be evaluated at 12 weeks and 24 weeks. 
Randomization will occur after enrollment, using a random assignment program, located on the PIs computer, 
with stratification based on history of PrEP (newly starting vs. already on PrEP > 3 months) and age (18-25 vs 
25 and older), since these factors may be associated with adherence and response to the intervention.   
The IMB Gaming Intervention.  The IMB Gaming Intervention is designed to improve information, 
motivation, and skills about adherence and HIV preventative behaviors throughout play (See Appendix 1, pp. 
2-17). All content will be chosen for its appropriateness for the target population and with refinements made 

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during the Development Phase. With input from the research team and PrEP users, we will produce a 
sensitive, stylistically and theoretically consistent intervention. Each level in Viral Combat provides new 
challenges and unique and colorful environments. However, the mission stays the same: kill virus and build 
strength through 1) taking medicine, 2) learning HIV prevention information, 3) engaging with healthy 
characters in order to improve motivation and build skills. Participants will be told to take PrEP daily and 
phones and software will be coded to record and react to daily dosing. If a participant misses a dose, a 
message is sent from the CleverCap dispenser to study investigators’ database on a secure server. This data 
is then read electronically by a CleverCap software program. This software in turn sends a game graphic with a 
supportive message such as “Missing you: Get in the Game” to the participant’s phone. A similar procedure 
and software have been successfully developed, implemented and utilized in our R01 HD074846. At all times 
during the study, participants in both conditions will be able to use their phone regularly, with all the features 
available to them within phone plan limits. Throughout the gaming intervention subjects will continue routine 
clinical care visits and HIV testing (as recommended by PrEP prescribing guidelines) in the PrEP clinic. The 
developed IMB game, Viral Combat, and the integration of the CleverCap dispenser with phone, are the two 
unique, necessary, and defining elements of the IMB Gaming Intervention. 
 Comparison condition (COMP): CleverCap and non-IMB iPhone game.  This condition will be matched 
with the IMB Gaming Intervention for appeal, time and attention. Subjects in COMP will each receive 
smartphones with the same data service plan as the active arm. Smartphones given to participants in COMP 
will have a stylistically similar non-PrEP, non-IMB game designed by Mission Critical Studios (Dr. Nano X: 
Incredible Voyage Inside The Body, http://www.youtube.com/watch?v=lyHzSZFzU1Q ). This is the same 
game that Viral Combat is being adapted from. Therefore, the iPhone game in COMP will have a look and feel 
that is very similar to our intervention game but without IMB, PrEP, and HIV prevention related content. 
Participants will also receive a CleverCap device, which records pill dispenser openings, but there will be no 
dose related messaging.  Similar to the Intervention group, participants will have routine clinical care visits in 
the PrEP clinic (or more frequently if needed for urgent care). 
  
Design Considerations  
Intervention contamination. Participants in the COMP condition could hear from those in the IMB 
Intervention about the IMB app/game but they will not have access to it on their phone. Although it is possible 
that the COMP participants could play the game once on an Intervention participant’s smartphone, it is unlikely 
to be a frequent occurrence. Nevertheless, we will assess familiarity and usage of the game by self report at 
follow-up. In addition, we will assess the occurrence of cross talk between subjects in the two conditions at 
follow-ups and adjust the analyses accordingly, if needed.  
Smartphones: access and confidentiality.  Data suggest that average adults and young adults have 
access to smartphones and studies suggest that within 2 years the majority of phones owned will have these 
application capabilities, so the IMB app/game will be designed for this almost universal technology. 
(37,39,40,55) Some participants will already have a smartphone, if it is not an iPhone or Android, we will 
provide them with a new study phone for the duration of their participation. The phone will be provided to 
minimize technical difficulties with the CleverCap data transfer and the operation of the game that is designed 
for iPhones and androids but not other devices. This ensures that all intervention subjects have the same 
gaming experience with the same displays, graphics, sounds and controls. Loss of a phone is possible but 
other studies suggest that it is infrequent.(121,122) In our ART adherence study utilizing iPhones given to 
participants, not one phone was lost throughout the development stage and open trial. Participants report they 
are motivated to care for the phone because it becomes theirs after the study period. The phone will be 
password protected, so call logs and texts will not be accessible. None of our technology partners: Mission 
Critical Studios, Compliance Meds Technologies, LLC, or the phone carrier will have PHI data. There will be no 
link to personal subject information because all phones will be purchased by a hospital account and linked 
back only to the hospital/PI. Only the PI will have the linkage of phone (designated by product number) with 
participant name. This information will be stored and destroyed following the same HIPPA and IRB procedures 
as all other personal data collected (See Human Subjects).  
Assessments. All assessments will take place in a quiet room near or in the PrEP clinic. Complete 
assessments of attitudes and behavior will occur at baseline, 12 weeks and 24 weeks, and will take 45 minutes 
to complete. Clinic records will also be coded for biologic outcomes at these 3 assessments. We will use 
tracking procedures (See Sample and Recruitment) to maintain contact.  

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Measures. An audio-assisted computer self-interview (ACASI) will be used to assess behavior since it is 
confidential, allows for complex branching/skip patterns, and detects greater rates of risk behavior.(123) 
Standard instruments will be administered to gather demographic data (including age, educational level, sexual 
orientation, SES, race, ethnicity and stability of housing).  The measures below will be used to evaluate HIV 
related knowledge, attitudes, and risk behavior (see Table 1 below for linkage to constructs and intervention). 
 
 
 
 
Table 1. Linkage between constructs, intervention foci, and assessment instruments  
 
Primary outcome (measured daily by CleverCap): 
CleverCap openings. The number of days participants take doses correctly in each of the six months will 
be our primary outcome. The data is collected wirelessly by CleverCap, and stored daily on a HIPAA compliant 
server as previously described. 
Secondary outcomes (measured at baseline, 12 and 24 weeks): 
Self-report of PrEP adherence. This consists of two items: “How many days in the past month did you 
miss or not take your PrEP medication?”  and “How many days in the past week did you miss or not take your 
PrEP medication?”  
ARV (TFV-DP and FTC-TP) levels. Intracellular TFV-DP and FTC-TP will be measured in red blood cells 
using dried blood spots. TFV-DP levels provide a measure of long-term adherence over the preceding month 
(like hemoglobin A1C) and a detectable FTC-TP provides information about recent dosing (i.e. if FTC-TP is 
detectable, a recent dose was ingested Y/N). The level of intracellular TFV-DP can be used to estimate how 
many doses/week the participant is taking on average (eg 7/wk on average, 4-7/wk on average, 2-4/wk on 
average, <2/wk on average). 25µL will be drawn each time. The blood samples will be sent to Skaggs School 
of Pharmacy and Pharmaceutical Sciences at The University of Colorado Aschutz Medical Campus. TFV-DP 
and FTC-TP levels and laboratory analyses will be done by Peter Anderson, Pharm.D who is the leading 
expert in conducting and interpreting these results.(148)  
Medical history. Staff will abstract from the clinic record the number of medical visits kept and missed in 
the past 12 weeks.  
The Risk Behavior Assessment. The RBA (used in Dr. Brown’s other federally-funded projects) is a 
reliable and valid computer-assisted structured interview assessing self-reported sexual behaviors. It assesses 
type of sexual behavior (i.e., anal, oral, vaginal) in the past 12 weeks, frequency of sex, and number and 
gender of partners. Additional questions cover sex with high-risk partners, frequency and quantity of substance 
use and having sex while using alcohol/drugs.(132)   
IMB construct outcomes (measured at baseline, 12 and 24 weeks): 
HIV & STI knowledge. The HIV Knowledge Scale assesses knowledge about issues such as risks for HIV, 
using 18 items with “true,” “false,” or “do not know” response options. Test-retest reliability (r=0.73) and internal 
consistency (alpha=0.90) were satisfactory in studies with at-risk young adults.(43) The STI Knowledge 
Questionnaire uses similar response options with 10 items assessing risk for and treatment of sexually 
transmitted infections. Test-retest reliability (r=0.88) and internal consistency (alpha= 0.86) were both 
satisfactory in studies with at-risk young adults (Appendix 2, pp. 29-30).(44) 
Attitudes towards adherence. This checklist was from attitude items used from several AIDS Clinical 
Trials Groups and will be modified to reflect adherence to a medication to prevent HIV. The checklist assesses 
IMB Constructs 
 Intervention Foci 
Assessment Instruments 
Information: about HIV/STI sexual risk 
knowledge 
 
Motivation: for adherence and risk 
attitudes and intentions  
 
 
Behavior: medical adherence, sexual 
risk, behavioral self-efficacy 
 HIV knowledge, Perceived 
vulnerability to HIV/STIs 
 
 Motivation for adherence 
 Motivation for safer sex 
 Perceived barriers 
 
 Medication and visit 
adherence, safer sex skills  
HIV/STI knowledge scales 
 
 
Adherence & risk attitudes scales 
 
 
CleverCap dispenser openings, 
adherence and sexual risk self report, 
ARV levels, 
self-efficacy for adherence and sexual 
safety 

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16 common barriers to taking ARV as prescribed and 10 aids to taking ARV. The original measure is being 
used in several on-going trials (see Appendix 2, pp.31-38). 
Motivational readiness for adherence.  Rollnick’s Readiness Ruler (127) will be used to assess 
motivation for adherence to medication and medical visits.  Respondents rate how ready they are to take PrEP 
as prescribed and to keep medical appointments on two items from 1 (not ready) to 10 (ready to be consistent 
or already consistent) each month.  Subjects will also complete the 10 item Likert-style IMB PrEP Motivation 
Scale from the LifeWindows Project Team. It will be modified to assess personal and social motivations for 
PrEP, rather than ART (Appendix 2, pp. 39-40).(125) 
Medication & appointment self-efficacy.  This measure was developed based on Bandura’s (1986) 
theory of self-efficacy(89) and was shown to have strong reliability (alpha>0.8) in a study of HIV medication 
adherence.(128) The instrument consists of Likert style items (with five response options). Three items assess 
self efficacy for taking medication as prescribed and three items assess self efficacy for adherence to medical 
appointments (Appendix 2, pp. 36-37). IMB PrEP Behavioral Skills Scale has 14 Likert style items and will be 
modified to assess perception of the ability to perform the necessary PrEP skills rather than ART skills. It has 
an internal consistency of 0.9 with infected adults (Appendix 2, pp. 41-42).(125) 
 
Demographics and Sample Characteristics (measured at baseline, 12 and 24 weeks). We will assess 
these factors to further characterize the sample.  
Relationship with Providers. This five item measure assesses the perceived relationship with health care 
providers using Likert type items suggested by an ART adherence intervention with adults (Project HEART) 
(Appendix 2, pp. 34-35).(129)  
Social Support for Medication Adherence. This six item measure assesses social support for taking 
medications, going to medical appointments and other tasks related to adherence using Likert style items with 
a four point scale. It is being used in AIDS Clinical Trials studies.  A single score for social support can be 
generated from these items or single items can be analyzed, such as support for medical appointments, as this 
project will do (See Appendix 2, pp. 37-38).  
Brief Symptom Inventory. Mental health issues will be assessed by the Brief Symptom Inventory (BSI), 
which requires only eight to ten minutes in which to complete. It yields nine primary symptom scales and global 
indices and has norms for adolescents and adults.  The reliability, validity, and utility of the BSI has been 
extensively tested and internal consistency for the sub-scales (dimensions) range from .71 to .85.(130)  
The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST V2.0). The ASSIST is an 
eight item questionnaire that screens for all levels of problem substance use.  The instrument covers tobacco, 
alcohol, cannabis, cocaine, amphetamine-type stimulants (including ecstasy), inhalants, sedatives, 
hallucinogens, opioids and “other drugs.”  It demonstrates significant concurrent, construct, predictive and 
discriminative validity and it is able to discriminate between low, moderate and high risk use.(131) 
 
Data Analytic Plan 
Hypothesis One: The IMB Adherence Intervention will be judged by participants to be feasible, appealing, 
relevant, and useful. A total of 40 qualitative interviews during the Development Phase will assess acceptability 
and appeal of the Intervention, and 20 of the subjects will also complete an open trial of the intervention for 
perceived feasibility, participant motivation and engagement (See Appendix 2, pp. 43-52). We will review the 
interviews for any game material that is unfavorable to participants and we will make revisions. Any game 
modules that receive a mean score on the Session Evaluation Form that is <20 (smaller scores = less 
satisfaction) will be reviewed to determine what content should be revised, changed or discarded.  
Hypothesis Two: Compared to subjects in the control group, participants in the IMB Gaming Intervention 
will show: improved adherence, improvements in biological measures (TFV-DP and FTC-TP), decreased HIV 
risk behaviors, greater increases in HIV knowledge, improved self efficacy and improved attitudes for treatment 
adherence. The primary outcome (number of doses taken correctly recorded by CleverCap) will be analyzed 
as the count of correct doses taken each month for the six study months. Generalized estimation equations 
(GEE) with a Poisson distribution and log link function will be used to model outcomes with a count distribution. 
The GEE analysis will account for nesting of assessments within participants and allows for data that follow 
non-normal distributions. Secondary outcomes that have count data (self report of adherence, unprotected sex, 
medical appointments) will be similarly analyzed. The IMB constructs and levels of TFV are continuous 
variables and will be evaluated using Repeated Measures Analysis of Variance (RMANOVA). FTC levels 
reveal a recent ingestion (yes/no) and will be analyzed by tests of proportional difference. Dr. Anderson will 

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consult on appropriate analyses for TFV and FTC. In all analyses, we will test for differences in linear change 
over time between intervention and control groups on each outcome variable. We will examine baseline 
differences across all outcome measures to assure that randomization was successful and that groups were 
equivalent at baseline. We will control for demographic variables that show pretest differences.  
Power. As this is an intervention development study and the impact of the experimental intervention is not 
known, there may not be adequate power to determine the efficacy of the IMB Gaming Intervention and pilot 
studies are not designed to provide accurate estimates of effect sizes upon which to base large trials.(135) 
Nevertheless, the pilot RCT may provide a “signal” of impact on outcomes and IMB constructs.  Power was 
estimated using Monte Carlo simulation in Mplus 7.11. We assume 85% retention over the trial period. For the 
primary outcome, assuming an initial rate of 16 doses per month, this study will have power of .80 to detect a 
rate ratio of 1.28. In other words, this study will be able to detect an increase from 16 to 20 doses per month 
(one additional dose each week), assuming the control group maintains at 16 doses per month. For the 
RMANOVAs, this study will have power to detect a large effect size (Cohen’s d = .80). 
Protection of Human Subjects and Safety Monitoring Plan 
 
Human Subjects Involvement, Characteristics and Design 
 
The proposed research study is comprised of two phases. Firstly, a Development Phase (n=40, 18 years 
of age and older, receiving PrEP) in which we will conduct formative research to guide the development of the 
IMB game and conduct an open trial in which the integration of the Information-Motivation-Behavioral Skills 
(IMB) based game and the CleverCap electronic dispenser is implemented. Secondly, a Controlled Trial 
Phase in which we will evaluate the preliminary efficacy of the IMB Gaming Intervention compared to a 
comparison condition (n=50, 18 yrs of age and older, receiving PrEP). Subjects will be recruited from the PrEP 
clinic at Miriam Hospital (See Facilities and Other Resources).  A project activities timeline is in the Budget 
Justification section.  
 
Inclusion Criteria.  All male persons on PrEP over the age of 18 yrs old, will be eligible for enrollment in 
each phase of study according to the following criteria: 1) English speaking, 2) receiving prophylactic 
antiretroviral treatment, 3) not enrolled in another PrEP related study, and 4) able to give consent/assent and 
not impaired by cognitive or medical limitations as per clinical assessment. There will not be overlap between 
subjects in the Development Phases and Controlled Trial Phase.  
  
Rationale for Including Special Classes of Subjects.  The age, gender, and medical status of our 
participants are dictated by the need for research in the area of HIV prevention for young adults and adults at 
risk for HIV. 
 
Sources of Materials 
 
Research Material Obtained from Living Human Subjects.  Research material obtained from 
participants include the following 1) all questionnaire data, 2) audio-tapes from qualitative interviews, 3) ARV 
blood levels, 4) adherence data collected from the CleverCap dispenser, 5) subject engagement with IMB 
game. For the Development Phase, subjects will complete qualitative interviews in-person regarding their 
reactions to the IMB informed game and its integration with the wise pill dispenser. These interviews will be 
recorded and they will take place at the Miriam Hospital. The audio-taped interview and written surveys of their 
reactions to the Intervention will be the sources of material for this phase. For both the Pilot and Randomized 
Controlled Trial study phases, participants will complete questionnaires about their demographic information, 
sexual behavior, adherence behaviors, and attitudes. Questionnaires will be completed at entry to the study 
and at 12 and 24 week assessments.  Biological measures will also be obtained during routine clinical care, 
and used as outcome data during the RCT phase of the study. The 12 and 24 week assessments and the 
collection of biological data will be done in the Miriam Hospital Clinical care areas, in designated clinical 
spaces that are HIPAA compliant. Engagement in game analyses, provided by Mission Critical Studios will be 
participant non-specific and generalized. For example, Mission Critical Studios can collect data on game usage 
like any other app or website owner that shows percentage of times players of the game complete levels, 
percentage of players that stop using the game in particular places. For example data collected by Mission 
Critical studios would state: x% of players quit the game in the skin Level, or x% of players stop playing the 

Version 9.14.2016 
game after 7 minutes. This data is not linked to a particular participant, and is not linked to the particular phone 
in use, which is designated as owned by lifespan (not the study patient/participant). This gaming data is not 
connected or linked to any participant’s name, demographic information or health status/diagnosis. Adherence 
data connected to a CleverCap device is also not linked to participant name, demographic information, health 
status or diagnosis. An example of CleverCap data is the following. CleverCap ID 76781 opening 1/2/12, 1 
opening 1/3/12, etc.  
 
Linkages to Subjects and Access to Subject Identities.  For each stage of the research, participant 
names and contact information will be maintained in a recruitment/enrollment database during the course of 
the study.  Once individuals enroll in the study, names will be linked to participant ID number in this database, 
which will be kept in a restricted access folder on a secure server. All name/ID number files will be assigned a 
code name unrelated to the name of the study. All phones will be purchased by the Lifespan 
Corporation/Rhode Island Hospital and the phone contract will have only Lifespan/Rhode Island Hospital 
recorded as the designated owner of the iPhone. Study personnel will designate participant’s iPhone by 
assigning the iPhone the participant’s ID number and this linkage will again be accessible only to study 
personnel. A similar process will occur with CleverCap adherence data. Subjects will be linked to CleverCap 
adherence technology and measurements by ID number only. CleverCap maintains a secure, HIPAA 
compliant data transfer platform and there is no identifying, or demographic information linked to a patient 
using a CleverCap dispenser. Access to adherence data measured by CleverCap is only granted to approved 
study personnel on a secure network. Names of medications, names of study participants, or name of the 
study not collected or recorded in the CleverCap network. Only pill opening events, designated by a CleverCap 
ID number, are recorded in their database. In the case of investigator needing technological assistance (for an 
individual’s phone, smart cap, or game (CleverCap, Mission Critical Studios), study personnel will only refer to 
a individual’s phone or technology by the ID number for that particular technology, not by the participant’s 
name. For example “CleverCap ID number 7678 is not working properly.” Signed consent and assent forms will 
also be kept in a locked file cabinet, separate from any other project data.  Once data collection is completed, 
the corresponding recruitment/enrollment database will be deleted, as it is unnecessary to maintain the link 
between participant identity and study data. Destruction of the Master Clinic Patient Lists must be witnessed 
and documented on the Master List Verification of Destruction document, which will be maintained in the site’s 
regulatory files. Furthermore, any information collected as part of this study will be accessible only to research 
staff that has completed mandatory training in the protection of human subjects.  
 
Potential Risks 
 
 
Every effort will be made to ensure that study participants are protected from risks.  The risks are as 
follows: 1) potential coercion, 2) loss of confidentiality, 3) emotional discomfort during the assessment and/or 
program sessions, 4) medical complications from venipuncture. The protection against each risk is described in 
detail below under Adequacy of Protection Against Risk. 
 
 
Adequacy of Protection Against Risk  
 
Recruitment and Informed Consent. The risk of potential coercion will be minimized by following 
standard procedures for obtaining the informed consent. Study personnel will fully explain the study 
procedures, risks, benefits, and alternatives to participants. Participants will also be reminded that study 
participation is voluntary and that refusing to participate or withdrawing from the study at any time will not result 
in any negative consequences. Recruitment for all phases of the project (Development Phase and 
Randomized Controlled Trial Phase) will involve the same screening procedures. Research staff will search for 
participants who are eligible for the study in the clinical setting of their routine care: Miriam Hospital STI/HIV 
Testing and Prevention Clinic. Subjects will be assured that their routine clinical care will not be disrupted, or 
negatively affected, by their choice to participate or not participate in the study. Subjects approached about the 
study will be approached and consented regarding the phase of the study that is relevant at that time (i.e. 
qualitative interviews, open trial, or randomized controlled trial). In all cases above, participants will be assured 
that they are free to withdraw from the study at any time and that if they do withdraw any data collected up to 
that point will be destroyed/stripped from any data files (see Protection Against Risk for data handling 
procedures).   

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Protections Against Risk 
 
Breach of Confidentiality. Potential risk will be minimized by strictly adhering to the guidelines for 
research outlined by the Lifespan IRB, Rhode Island state law, the Federal Health Insurance Portability and 
Accountability Act of 1996 and its regulations (“HIPAA”), and the DHHS Federal Policy for the Protection of 
Human Subjects (45 CFR Part 46 Subpart D). This will include identifying participant research data by numeric 
ID only and maintaining any records containing potentially-identifying information separate from any research 
data. All research data (written records and audiotapes of program sessions) will be kept in a locked file and 
electronic data will be password-protected. All of these study-related materials will only be accessible to 
research staff.  No names, only identification codes, will be used in presenting data in lectures, seminars, and 
papers.  Information will be released only with written consent of the parent/guardian.  
 
All data collection will take place in secure and supervised clinical settings at the Miriam Hospital. All 
study personnel on this application have completed training and received certification in Human Subjects 
Research Protection (CITI Program) and HIPAA regulations. They will continue to renew this training in 
compliance with hospital policies.  
 
Participants will be asked to provide informed written consent to audiotaping at the time of study entry if 
they are participating in the qualitative interviews during the Development Stage. To assure confidentiality and 
protection of the participants during audiotaping, all tapes will be stored in locked file cabinets in a secured 
office. Only Drs. Whitely and Brown will have access to the audiotapes so that ongoing guidance can be 
provided as to the conduct and design of the study. 
 
To further protect the privacy of the study participants, we will obtain a Certificate of Confidentiality from 
the U.S. Department of Health and Human Services (DHHS).  With this Certificate in place, the researchers 
cannot be forced to turn over identifying information about a study participant in any federal, state, or local 
criminal, administrative, legislative, or other proceedings.  This Certificate does not prevent a study participant 
from volunteering to turn over their research information nor does it prevent researchers from providing 
research-related information to others when requested by the study participant. 
 
 
Emotional Distress. We will minimize distress by presenting questions/program techniques in a 
supportive manner, assuring participants that they may refuse to answer any questions that make them 
uncomfortable, and may terminate participation in the intervention at any time. All subjects may receive 
medical or mental health treatment at any time during the study. Clinical need will determine whether it is 
appropriate for the participant to stop continuation in the study. 
 
If a participant reports feeling distressed, or has any acute concerns, as a result of their involvement in 
any phase of the research project (i.e. consenting, baseline assessment, interview session, follow-up, 
collection of biological data), clinical resources will be offered on-site. The clinical locations used in this study 
are ideal as they each provide easy access to medical and mental health clinicians.   If a subject contacts 
study staff because of distress or concern due to participation in the study or directed activities that occur away 
from the clinical space  (such as a concern that phone use or activities led to a dispute), the subject will be 
assessed first over the phone, and then, if needed, as described below.  
 
During any phase of the study, if research staff determines that a participant is an acute medical or 
psychiatric risk, the PI or licensed designee will meet with the participant individually for further assessment of 
any clinical needs. Acute risks would include severe medical illness, or the development of any other severe 
psychiatric symptoms or disclosure of sexual or physical abuse.  Any subjects who exhibit acute risks will be 
evaluated immediately by emergency room clinical staff at Miriam hospital, or if less acute, by an independent 
clinician that day. Less severe medical needs or distress can be managed by staff or PI over the phone or with 
an individual interview. The PI and/or staff will meet with participants to review concerns and to make referrals 
for continuing care as needed. Of note, members of the proposed research team have substantial prior clinical 
(medical and psychiatric) and research experience in care of young adults and adults as evidenced through 
their biographical sketches.  
 
 
Complications from Venipuncture. Participants will require venipuncture to collect blood samples for 
ARV blood level tests to be performed. This procedure may cause local discomfort, bleeding, or bruising; rarely 
small clot or infection can occur at the blood draw site. This assessment should not be considered greater than 
minimal risk in and of itself given its routine use in general health care delivery. However, if a medical 

Version 9.14.2016 
complication occurs, the patient will be given immediate and appropriate clinical care as described above. Any 
subject who exhibit acute risks will be evaluated immediately by emergency room clinical staff at Miriam 
Hospital, or if less acute, by an independent clinician that day. 
 
 
Potential Benefits of the Proposed Research to the Subjects and Others 
 
  
Importance of Knowledge to be Gained. All phases of the proposed study will provide important 
information for PrEP related intervention development. We hope that our intervention will be successful in 
improving treatment adherence and reducing HIV in our subject population and think that the clear examination 
of these questions outweighs the previously mentioned risks.  The effectiveness of a novel, scalable, 
technology driven, intervention integrated into treatment with PrEP is understudied. Given the significant health 
sequelae associated with HIV infections, and the paucity of data on PrEP related adherence and behavioral 
intervention programs, the knowledge to be gained from this research is significant.  The risks to participants 
are reasonable in relation to the importance of the knowledge to be gained. 
 
 
Reimbursement for Time and Effort.  Subjects will be reimbursed $50 for each qualitative interview 
during the Development phase.  During the Interview phase, participants will be reimbursed $5 for every level 
of the game they complete, up to $30.  Subjects will be reimbursed $50 for their baseline and 12 week 
assessments during the Open Trial and $50 for a qualitative interview at 12 weeks. During the RCT phase 
subjects will be reimbursed $50 for baseline, 12 week, and 24 week assessments. Each participant in the open 
trial and RCT will also receive an iPhone with a paid data service plan for the study duration (iPhone 4S: $100, 
data package through Lifespan/ AT&T $60/month). 
 
Data and Safety Monitoring Plan  
 
The nature of the population warrants the development of a Data Safety and Monitoring Plan.  To address 
the NIH policy for Data and Safety Monitoring, the PI has developed a system for oversight of the proposed 
study and its participants.  The Data and Safety Monitoring Plan for this application will begin by implementing 
standard procedures for day-to-day monitoring of the study.  Weekly meetings with the research team will be 
conducted to evaluate the progress of the trial and to review data quality, recruitment, study retention, and 
examine other factors that may affect outcome.  Participant experiences with the study procedures and the 
rates of adverse events will also be reviewed to determine any changes in participant risk.  The PI will 
immediately report any adverse events that are observed to the Lifespan Internal Review Board (IRB) and 
NIMH.  Serious adverse events (SAEs) will be reported to the Lifespan IRB immediately by telephone and by 
written report within 24 hours of our receipt of information regarding the event; SAEs will also be reported in 
writing to NIMH. Actions taken by the IRB in response to SAEs will also be reported to NIMH, as will reports of 
changes or amendments to the protocol as a result of an SAE.  Reports of changes or amendments to the 
protocol in general must be requested first in writing to the Lifespan IRB, which then will grant or deny 
permission to make the requested change or amendment in protocol.  Modifications to study aims or design 
will also be submitted to NIMH for approval prior to instituting them. Finally, if significant medical or mental 
health risks occur during the study period evaluation by the Miriam hospital emergency department will be 
immediately initiated to determine whether hospitalization or urgent care is needed. In the event that a 
research participant either withdraws from the study or the investigator decides to discontinue a research 
participant due to SAE, the research participant will be monitored by the investigator via ongoing status 
assessment until either a resolution is reached (i.e. the problem requiring hospitalization has resolved or 
stabilized with no further changes expected), the SAE is determined to be clearly unrelated to the study 
intervention, or the SAE results in death. Outcome of all SAEs will be periodically reported to NIMH. A 
summary of the SAEs that occurred during the previous year will be included in the annual progress report to 
NIMH. 
 
Educational Training 
 
Since October 1, 2001, Lifespan has required that researchers and IRB members read Protecting Study 
Volunteers in Research (Dunn & Chadwick) and complete the related exam.  This process has served as an 

Version 9.14.2016 
initial certification. In June, 2005, the Office of Research Administration contracted with CITI, a Collaborative 
Institutional (modular) Training Initiative program, for our Human Subjects Protection and HIPAA training for all 
research personnel.  Currently this program offers researchers a basic human subject's protection course as 
well as a refresher course that is required every three years.  Documentation of successful completion is 
automatically generated and can be printed directly by the researcher 
Additional and continuing education opportunities for clinical researchers include the Office of Research 
Administration newsletter that is circulated to > 900 recipients every 6 weeks. Relevant information concerning 
research review is available on the ORA web page at www.lifespan.org/research/. In addition to standard 
institutional research information, the web page contains links to other sites such as CenterWatch, NIH, 
PRIM&R/ARENA. 
 
 
Inclusion of Women and Minorities 
 
Women.  Women will not be included in this study because this research focuses on the most at risk 
population for acquiring HIV in the U.S., MSM.  The PrEP clinic at Miriam Hospital has prescribed PrEP to 
MSM only at this time. It is anticipated that approximately 100% of the sample will be males, reflecting the 
population of the PrEP clinic from which the sample will be recruited, so women will not be represented. 
Selection of only MSM for this study allows the iPhone app to be tailored to their specific needs as is 
appropriate for this phase of research. 
 
Minorities.  The aim of our recruitment strategy is for the resulting program materials to be appropriate for 
racial and ethnic minorities. We anticipate that in terms of race 65% of the enrolled participants will self-identify 
as Black/African American and 30% will self-identify as Hispanic or Latino.  
 
Inclusion of Children 
 
Children.  Approximately 25% of the participants in this study will be comprised of youth ages 18-21. 
Currently, the gaming content selected in the intervention has been designed for children 18 and older. 
Preliminary sessions are therefore designed to be appropriate for the developmental and cognitive level of 
youth. Thus, the proposed program is appropriate for children as defined by NIH. During the Development 
Phase, intervention material and content will be further tailored to the developmental and cognitive level of our 
participants.