The Effect of opt-in Versus Opt-out Framing on Clinical Trial Enrollment Among Patients With Peripheral Artery Disease
Phase: NA
Conditions: Peripheral Artery Disease
Sponsor: University of Pennsylvania

Opt-in versus opt-out clinical trial enrollment  
among patients with peripheral artery disease: 
A GAME PAD substudy 
 
 
Version 2  
November 09, 2020 
 
 

1. 
Background 
Research studies are hampered by low participation rates, threatening these studies’ external 
validity, prolonging study timelines, and increasing costs.(1,2) Behavioral economics research 
has shown that framing retirement savings and organ donation participation as opt-out rather 
than opt-in increases participation in these programs while maintaining informed choice.(3) In 
healthcare, an opt-out approach has also been shown to increase influenza vaccination and 
human immunodeficiency virus screening.(4,5) More recently, a randomized controlled trial 
testing opt-in versus opt-out approaches to colorectal cancer screening by fecal occult blood 
testing showed that the opt-out approach increased participation rates nearly 3-fold.(6)  
In clinical trials of home-based monitoring for patients with myocardial infarction and a 
behavioral intervention for patients with poorly-controlled diabetes mellitus, sub-studies have 
shown that an opt-out approach increased enrollment compared with an opt-in approach.(7,8) In 
a trial of a home-based monitoring program for patients with myocardial infarction, eligible 
patients were enrolled using a traditional opt-in approach.(7) These patients were sent a 
recruitment letter after their myocardial infarction, contacted via phone and consented for 
enrollment, and, after consent, sent a remote monitoring medication bottles, entered into a 
system configured with financial incentives, reminders, and social support. A separate cohort of 
patients, made ineligible for participation by their insurance type, was sent configured 
medication bottles along with their recruitment letters to create an opt-out frame. In the opt-in 
arm, 16% of patients agreed to participate in the study, compared with 38% in the opt-out arm. In 
a trial of a behavioral intervention for patients with poorly controlled diabetes mellitus, patients 
were randomized to receive a letter informing them that they had been enrolled in a clinical trial 
(opt-out) versus a standard recruitment letter (opt-in).(8) In the opt-in arm, 13% of patients 
agreed to participate compared with 38% in the opt-out arm.  
Though opt-out trial participation has increased enrollment in two prior studies, it is uncertain 
whether it will do the same in a clinical trial intended to promote physical activity in patients 
with peripheral artery disease (PAD), as these patients differ from those included in the 
myocardial infarction and diabetes trial in several ways, and the intervention differs as well. We 
therefore seek to conduct a randomized substudy of the proposed GAME PAD randomized 
controlled trial, evaluating the effect of opt-out versus opt-in framing of clinical trial enrollment.  
2. 
Study Objectives 
The objectives of this study are the following: 
1. To determine the effect of an opt-out versus an opt-in approach to enrollment in a clinical 
trial enrolling patients with peripheral artery disease on the proportion of patients 
contacted enrolled 
2. To determine the effect of an opt-out versus an opt-in approach to enrollment in a clinical 
trial enrolling patients with peripheral artery disease on the clinical characteristics of 
patients who decide to enroll in the study 
 
3. Sub-Study Design and Procedures 
3.1  
General overview 

The GAME PAD study is a two-arm randomized controlled trial aimed at evaluating whether a 
home-based walking program with automated coaching augmented with gamification and 
behavioral economic principles improves functional capacity in patients with PAD. The study 
will randomize 100 patients with PAD to a 16-week home-based walking program using goal-
setting alone (attention control) or to the same home-based walking program with automated 
coaching augmented with gamification and behavioral economic principles. The study will be 
conducted using the Way to Health platform, and patients will enroll and consent for 
participation online, with available help from a study coordinator by telephone. This sub-study 
will test whether opt-in or opt-out framing of study participation upon initial contact affects the 
proportion of patients who ultimately enroll in the study and the demographic characteristics of 
enrolled patients. 
3.2.  
Site 
This GAME PAD substudy will enroll patients from the University of Pennsylvania Health 
System, which consists of five large hospitals including the Hospital of the University of 
Pennsylvania, Penn Presbyterian Medical Center, Pennsylvania Hospital, and Chester County 
Hospital. 
 
3.3.  
Patient Selection Criteria 
Patients are eligible to be included in the study if they are ≥ 18 years of age, have been seen in 
the University of Pennsylvania Health System, and have an ICD-10 code consistent with 
peripheral artery disease (I70.2x, I70.3x-I70.7x, I73.9) or peripheral artery disease on their 
problem list. There are no exclusion criteria. 
Please refer to the separate protocol for inclusion and exclusion criteria for the main GAME 
PAD study. 
 
3.4.  
Substudy procedures 
3.4.1 Randomization  
Eligible patients will be contacted via email to determine their interest in participation in the 
GAME PAD study. Patients will be randomized 3:1 to an email message framing trial 
participation in a standard opt-in manner versus an email message framing trial participation in 
an opt-out manner.   
 
3.4.2 Study arms 
Patients randomized to opt-in framing will be instructed to visit the Way to Health website to 
enroll in the study, or to call or email the study coordinator with questions or for assistance in 
enrolling. Patients randomized to opt-out framing will receive an email that frames participation 
in the study as part of the standard of care, and will be informed that a study coordinator will be 
calling them in the coming days to start enrollment in the study unless they opt out of 
participation.  
3.4.3 Data collection 
Baseline characteristics of patients randomized to each framing method will be abstracted from 
the electronic health record and Penn Data Store, and will include age, sex, race/ethnicity, and 
medical comorbidities. Whether contacted patients created an account on the Way to Health 
website and/or ultimately consented for enrollment in the study will be captured. 

 
3.4.4 Outcomes 
For all outcomes, we will compare patients initially presented with study participation via opt-in 
framing versus opt-out framing. The primary outcome will be the proportion of patients that 
enroll in the study. Exploratory outcomes, among patients that ultimately enrolled in the study, 
will include the proportion of enrolled patients that failed to complete the study, change in daily 
step count from baseline to the end of the GAME PAD intervention and the end of follow-up 
(overall and stratified by overall GAME PAD study arm – gamification intervention versus 
attention control), and change in patient-reported symptom scores from baseline to the end of the 
GAME PAD intervention and the end of follow-up (overall and stratified by overall GAME PAD 
study arm) 
 
3.4.5 Informed consent 
Because the trial tests different methods of approaching patients prior to enrollment, informed 
consent cannot feasibly be obtained and we will request a waiver of informed consent 
 
4. 
Statistical Analysis 
We will compare the primary outcome and attrition rate between patients initially presented with 
study participation via opt-in framing versus opt-out framing using the chi-square method. 
Change in step count from baseline through the intervention period and follow-up will be 
compared using paired t tests, as will change in patient reported symptom scores from baseline 
through the intervention period and the end of follow up. The primary outcome will be analyzed 
using the intention-to-treat principle, grouping patients by framing of study participation at initial 
contact. Other outcomes, among patients that ultimately enrolled in the GAME PAD study, will 
similarly group patients by framing of study participation at initial contact. 
5.  
Human Research Protection 
5.1  
Data confidentiality  
Paper-based records will be kept in a secure location and only be accessible to personnel 
involved in the study. Computer-based files will only be made available to personnel involved in 
the study through the use of access privileges and passwords. Wherever feasible, identifiers will 
be removed from study-related information. Precautions are in place to ensure the data are secure 
by using passwords and encryption, because the research involves web-based surveys.  
 
5.2  
Subject confidentiality  
Research material will be obtained from the electronic health record. The data to be collected 
include age, sex, race/ethnicity, and medical comorbidities. Research material that is obtained 
will be used for research purposes only. The study identification number, and not other 
identifying information, will be used on all data collection instruments. All study staff will be 
reminded to appreciate the confidential nature of the data collected and contained in these 
databases. The Penn Medicine Academic Computing Services (PMACS) will be the hub for the 
hardware and database infrastructure that will support the project and is where the Way to Health 
web portal is based. The PMACS is a joint effort of the University of Pennsylvania's Abramson 
Cancer Center, the Cardiovascular Institute, the Department of Pathology, and the Leonard Davis 
Institute. The PMACS provides a secure computing environment for a large volume of highly 
sensitive data, including clinical, genetic, socioeconomic, and financial information. Among the 

IT projects currently managed by PMACS are: (1) the capture and organization of complex, 
longitudinal clinical data via web and clinical applications portals from cancer patients enrolled 
in clinical trials; (2) the integration of genetic array databases and clinical data obtained from 
patients with cardiovascular disease; (3) computational biology and cytometry database 
management and analyses; (4) economic and health policy research using Medicare claims from 
over 40 million Medicare beneficiaries. PMACS requires all users of data or applications on 
PMACS servers to complete a PMACS-hosted cybersecurity awareness course annually, which 
stresses federal data security policies under data use agreements with the university. The 
curriculum includes Health Insurance Portability and Accountability Act (HIPAA) training and 
covers secure data transfer, passwords, computer security habits and knowledge of what 
constitutes misuse or inappropriate use of the server. We will implement multiple, redundant 
protective measures to guarantee the privacy and security of the participant data. All 
investigators and research staff with direct access to the identifiable data will be required to 
undergo annual responsible conduct of research, cybersecurity, and HIPAA certification in 
accordance with University of Pennsylvania 334 regulations. Data will be stored, managed, and 
analyzed on a secure, encrypted server behind the University of Pennsylvania Health System 
(UPHS) firewall. This server was created for projects conducted by the Penn Medicine Nudge 
Unit related to physician and patient behavior at UPHS. All study personnel that will use this 
data are listed on the IRB application and have completed training in HIPAA standards and the 
CITI human subjects research. Data access will be password protected. Whenever possible, data 
will be deidentified for analysis.  
 
5.3  
Subject privacy  
For the purposes of this sub-study, participants will not engage in any study-related procedures 
where privacy could be violatd. 
 
5.4  
Data disclosure  
The following entities, besides the members of the research team, may receive protected health 
information (PHI) for this research study: The Office of Human Research Protections at the 
University of Pennsylvania -Federal and state agencies (for example, the Department of Health 
and Human Services, the National Institutes of Health, and/or the Office 364 for Human 
Research Protections), or other domestic or foreign government bodies if required by 365 law 
and/or necessary for oversight purposes.  
 
5.5  
Data safety and monitoring  
The Principal Investigator will be responsible for monitoring the study. For the purposes of this 
sub-study, participants will not engage in any study-related procedures, and risk will be minimal. 
 
5.6  
Risk/benefit  
5.6.1  Potential study risks  
The only risk posed to participants is breach of confidentiality. We will minimize this risk by 
using secure data methods as described previously.  
 
5.6.2  Potential study benefits  
No benefits are expected to accrue to participants in the study. However, better understanding the 
effect of opt-out design on clinical trial participation has the potential to increase clinical trial 

participation in the future, increasing the representativeness and reducing the cost of future 
clinical trials.  
 
5.6.3  Risk/benefit assessment  
Anticipated risks of this study should be minimal and the risk/benefit ratio is very favorable. We 
have previously outlined the procedures that will be used to prevent a breach of participant data. 
 
6. 
References 
1.  
Califf RM, Harrington RA. American industry and the U.S. Cardiovascular Clinical 
Research Enterprise an appropriate analogy? Journal of the American College of Cardiology. 
2011 Aug 9;58(7):677–80.  
2.  
Fanaroff AC, Vora AN, Chen AY, Mathews R, Udell JA, Roe MT, et al. Hospital 
participation in clinical trials for patients with acute myocardial infarction: Results from the 
National Cardiovascular Data Registry. Am Heart J. 2019 Aug;214:184–93.  
3.  
Loewenstein G, Brennan T, Volpp KG. Asymmetric paternalism to improve health 
behaviors. JAMA. 2007 Nov 28;298(20):2415–7.  
4.  
Yudin MH, Moravac C, Shah RR. Influence of an “opt-out” test strategy and patient 
factors on human immunodeficiency virus screening in pregnancy. Obstet Gynecol. 2007 
Jul;110(1):81–6.  
5.  
Chapman GB, Li M, Colby H, Yoon H. Opting in vs opting out of influenza vaccination. 
JAMA. 2010 Jul 7;304(1):43–4.  
6.  
Mehta SJ, Khan T, Guerra C, Reitz C, McAuliffe T, Volpp KG, et al. A Randomized 
Controlled Trial of Opt-in Versus Opt-Out Colorectal Cancer Screening Outreach. Am J 
Gastroenterol. 2018;113(12):1848–54.  
7.  
Mehta SJ, Troxel AB, Marcus N, Jameson C, Taylor D, Asch DA, et al. Participation 
Rates With Opt-out Enrollment in a Remote Monitoring Intervention for Patients With 
Myocardial Infarction. JAMA Cardiol. 2016 01;1(7):847–8.  
8.  
Aysola J, Tahirovic E, Troxel AB, Asch DA, Gangemi K, Hodlofski AT, et al. A 
Randomized Controlled Trial of Opt-In Versus Opt-Out Enrollment Into a Diabetes Behavioral 
Intervention. Am J Health Promot. 2018;32(3):745–52.