Effect of hospital-at-home vs. traditional brick-and-mortar hospital care in acutely ill adults: study protocol for a pragmatic randomized controlled trial.

BACKGROUND: Delivering acute hospital care to patients at home might reduce costs and improve patient experience. Mayo Clinic's Advanced Care at Home (ACH) program is a novel virtual hybrid model of "Hospital at Home." This pragmatic randomized controlled non-inferiority trial aims to compare two acute care delivery models: ACH vs. traditional brick-and-mortar hospital care in acutely ill patients. METHODS: We aim to enroll 360 acutely ill adult patients (≥18 years) who are admitted to three hospitals in Arizona, Florida, and Wisconsin, two of which are academic medical centers and one is a community-based practice. The eligibility criteria will follow what is used in routine practice determined by local clinical teams, including clinical stability, social stability, health insurance plans, and zip codes. Patients will be randomized 1:1 to ACH or traditional inpatient care, stratified by site. The primary outcome is a composite outcome of all-cause mortality and 30-day readmission. Secondary outcomes include individual outcomes in the composite endpoint, fall with injury, medication errors, emergency room visit, transfer to intensive care unit (ICU), cost, the number of days alive out of hospital, and patient-reported quality of life. A mixed-methods study will be conducted with patients, clinicians, and other staff to investigate their experience. DISCUSSION: The pragmatic trial will examine a novel virtual hybrid model for delivering high-acuity medical care at home. The findings will inform patient selection and future large-scale implementation. TRIAL REGISTRATION: ClinicalTrials.gov NCT05212077. Registered on 27 January 2022.

The impact of COVID-19 on a large pragmatic clinical trial embedded in primary care.

INTRODUCTION: The COVID-19 pandemic had significant impact on clinical care and clinical trial operations, but the impact on decentralized pragmatic trials is unclear. The Diuretic Comparison Project (DCP) is a Point-of Care (POC) pragmatic trial testing whether chlorthalidone is superior to hydrochlorothiazide in preventing major cardiovascular (CV) events and non-cancer death. DCP utilized telephone consent, data collection from the electronic health record and Medicare, forwent study visits, and limited provider commitment beyond usual care. We assessed the impact of COVID-19 on recruitment, follow-up, data collection, and outcome ascertainment in DCP. METHODS: We compared data from two 8-month periods: Pre-Pandemic (July 2019-February 2020) and Mid-Pandemic (July 2020-February 2021). Consent and randomization rates, diuretic adherence, blood pressure (BP) and electrolyte follow-up rates, records of CV events, hospitalization, and death rates were compared. RESULTS: Providers participated at a lower rate mid-pandemic (65%) than pre-pandemic (71%), but more patients were contacted (7622 vs. 5363) and consented (3718 vs. 3048) mid-pandemic than pre-pandemic. Patients refilled medications and remained on their randomized diuretic equally (90%) in both periods. Overall, rates of BP, electrolyte measurements, and hospitalizations decreased mid-pandemic while deaths increased. CONCLUSIONS: While recruitment, enrollment, and adherence did not suffer during the pandemic, documented blood pressure checks and laboratory evaluations decreased, likely due to fewer in-person visits. VA hospitalizations decreased, despite a considerable number of COVID-related hospitalizations. This suggests changes in clinical care during the pandemic, but the limited impact on DCP's operations during a global pandemic is an important strength of POC trials. CLINICAL TRIAL REGISTRATION: NCT02185417.

Implementation Challenges for a Multisite Advance Care Planning Pragmatic Trial: Lessons Learned.

BACKGROUND/PROBLEM: Advance care planning (ACP) pragmatic trials are needed. PROPOSED SOLUTION: We determined key system-level activities to implement ACP interventions for a cluster-randomized pragmatic trial. We identified patients with serious illness from 50 primary care clinics across three University of California health systems using a validated algorithm. If patients lacked documented ACP within the last 3 years, they were eligible for an intervention: (Arm 1) an advance directive (AD); (Arm 2) AD + PREPAREforYourCare.org; (Arm 3) AD + PREPARE + lay health navigator outreach. Triggered by an appointment, we mailed and sent interventions through automated electronic health record (EHR) messaging. We collaborated with patients/caregivers, clinicians, payors, and national/health system leader advisors. We are currently finalizing 24 months follow-up data. OUTCOMES/METHODS: We used the Consolidated Framework for Implementation Research (CFIR) and Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) frameworks to track secular trends and implementation efforts. KEY MESSAGE/RESULTS: Required multisite, system-level activities: 1) obtaining leadership, legal/privacy, and EHR approvals; 2) standardizing ACP documentation; 3) providing clinician education; 3) validating an automated serious illness identification algorithm; 4) standardizing ACP messaging with input from over 100 key advisors; 5) monitoring secular trends (e.g., COVID); and 6) standardizing ACP workflows (e.g., scanned ADs). Of 8707 patients with serious illness, 6883 were eligible for an intervention. Across all arms, 99% received the mailed intervention, 78.3% had an active patient portal (64.2% opened intervention), and 90.5% of arm three patients (n = 2243) received navigator outreach. LESSONS LEARNED: Implementing a multisite health system-wide ACP program and pragmatic trial, with automated EHR-based cohort identification and intervention delivery, requires a high level of multidisciplinary key advisor engagement, standardization, and monitoring. These activities provide guidance for the implementation of other large-scale, population-based ACP efforts.

Using a Single Irb for Nih-Funded Multisite Trials

As clinical trials evolve, the oversight by Institutional Review Boards (IRBs) has also evolved to meet everexpanding needs for both efficiency and changing regulatory requirements in the protection of human subjects. The most significant regulatory change to occur was the change to the Revised Common Rule Research Provision (45 CFR 46.114(b)) that went into effect on 20 January 2020, requiring all cooperative research subject to the Common Rule to use a single Institutional Review Board (sIRB) to review the research. Since the Common Rule affects all federally funded research, clinical trialists performing multicenter trials using federal grants are now required to use an sIRB instead of individual IRBs at each research site in their trials. For those multicenter trialists, using an sIRB offers efficiencies in time and effort which can aid in bringing trial results to fruition both faster and at a lower cost while still providing protection to human subjects. While commercial sIRBs have been available for many years, sIRBs placed at academic institutions and health care systems are relatively new. They can offer the benefit of lower cost for trialists within an institution, and better overall trial management by having more frequent communication and discussion regarding trial issues as well as improved safety management through aggregate safety review. They can also offer increased speed of research review with cooperative planning between trialist and the sIRB representatives. This session will focus on the use of sIRBs from various perspectives to give the view from an academic sIRB, from end users of both an academic sIRB and a health system IRB, and guidance from a clinical regulatory specialist regarding maintaining a trial master file while using an sIRB. Mr. Jarrod Feld from the University of Iowa will present from his perspective as the External IRB Coordinator at the University of Iowa. Mr. Feld coordinates reliance and compliance for University of Iowa human research studies which use the University of Iowa Institutional Review Board as their sIRB, and studies where Iowa relies on another institutional IRB. Mr. Feld also provides guidance to investigators on using an sIRB. Using his experience, Mr. Feld will outline the nature of reliance agreements, discuss working with a range of local IRBs to develop understanding regarding the reliance program and outline best practices for using an sIRB, and discuss enhanced safety management oversight when using an sIRB for large multisite trial. Ms. Tina Neill-Hudson from the University of Iowa will present from her experience as the sIRB Liaison for both the Acute to Chronic Pain Signature (A2CPS) Consortium, an NIH (National Institutes of Health)- funded multisite observational trial, and the Fibromyalgia and TENS in Physical Therapy Study (FM TIPS) study, an NIH-funded embedded pragmatic clinical trial. Ms. Neill-Hudson works with relying sites on completing the necessary regulatory documents needed for reliance agreements and sIRB approval. Ms. Neill-Hudson will discuss the process for obtaining reliance for institutions who may or may not have local IRB oversight and provide examples of specific steps and procedures for obtaining sIRB approval in a timely manner. Ms. Neill-Hudson will speak to the importance of having an sIRB liaison on the study team and the use of SMART IRB. Ms. Catherine Gladden from MassGeneral Brigham will present on using an sIRB for multicenter NIHfunded trials. Ms. Gladden will discuss the use of a Consortium-level reliance agreement and role of the local IRBs. Ms. Gladden oversees the sIRB liaison team at the Coordinating Center for the NeuroNEXT Network and works with the sIRB and local IRBs to ensure local policies and requirements are followed while maintaining compliance with the sIRB and the NeuroNEXT reliance agreement. Ms. Gladden will be discussing best practices for using an sIRB in a multicenter trial and discuss the experience of using an sIRB in the safety management plan. Ms. Cynthia Diltz from the University of Iowa wi l present on the topic of managing a trial master file while using an sIRB. Ms. Diltz will speak on her experience with electronic trial master files versus hard copy master files, and in using commercial software for trial master file management. Using an electronic trial master file is a necessity in the scheme of using an sIRB to assist sponsors and individual clinical research sites to view Institutional Review Board documents in real time and to provide a single storage location for documentation of Institutional Review Board approvals and activities such as continuing review. This session is timely due to the change to the Common Rule mandating the use of an sIRB for all research subject to the Common Rule, which has the most significant impact on trialists at academic institutions and health care systems. In an era of the need for timely study results for use in addressing urgent public health policy concerns, using an sIRB is becoming a necessity. The speed with which clinical trials need to be managed by an IRB has accelerated during recent public health care crises, notably the COVID-19 pandemic. In addition, it is likely that there will be changes to local IRBs as the norm becomes using an sIRB for any research subject to the Common Rule. Investigators and clinical site staff will require education on the evolution of human subject's protection and research review happening at an sIRB instead of within their local IRBs, and assistance in understanding the process and planning for success will be crucial.

Accommodating ''History Effects'' in Long Duration, Multisite Clinical Trials to Ensure Relevant and Compelling Evidence

Over the course of a clinical trial, changes in the practice environment have the potential to reduce internal and external validity and impact change in patient outcomes. Such ''history effects''1 can take the form of changes in standard of care, clinical guidelines and recommendations, new drug/device availability in the marketplace, testing and screening procedures, and, as recently experienced, a global pandemic. Clinical trials conducted over many years are particularly susceptible to history effects. Such effects can impact foundational ability to continue a trial, including clinician equipoise and ability to implement trial interventions, necessitating awareness and action planning. For example, Curtis et al.2 acknowledged challenges with clinical guideline history effects and issued recommendations for addressing them such as consideration of participant wellbeing, stakeholder engagement, safety monitoring, review of guideline and policy changes, and development of rules for protocol changes. This session will explore how four multisite clinical trials conducted with VA Cooperative Studies Program sponsorship and coordination have weathered history effects during prolonged periods of enrollment. Topics to be covered include the implementation of pragmatic designs, monitoring of clinical guidelines, assessing control group treatment conditions, modifying protocols, adjusting quality assurance procedures, refining recruitment pathways, and training site investigators. The speakers, Study Chairs, will describe best practices and provide recommendations for navigating history effects in prolonged multisite clinical trials that can ensure outcomes remain relevant and compelling to inform public health at trial commencement. The CSP 2008/PTXRx study is a pragmatic, randomized, double-blind, placebo-controlled, multicenter clinical trial of Veteran patients with diabetic kidney disease (DKD) examining whether pentoxifylline (PTX), when added to usual care, can delay time to end-stage renal disease or death. Enrollment for the study began in 2019, and it is anticipated that 9 years of follow-up will be required to observe the required number of primary events. Given the long duration of the study, changes in clinical guidelines were anticipated and have occurred, including the approval of new DKD therapies and introduction of a new formula for estimated glomerular filtration rate (eGFR) calculation. In anticipation of these changes, the study design allows for whatever standard of care is extant at any time during the course of the study. PTXR's pragmatic trial design and protocol leverage the VA's research infrastructure and remote platforms allowing the study to be responsive to external changes and to safely continue during a global pandemic. The CSP 596/OPTION study is a randomized, double- blind, multicenter trial of Veteran patients with a first or second recurrent Clostridium difficile infection (CDI) comparing (1) fidaxomicin and (2) vancomycin, followed by a taper and pulse to (3) a standard vancomycin regimen. Since enrollment began in 2016, significant changes in CDI epidemiology and clinical management have impacted the study. The COVID-19 pandemic also resulted in an administrative hold on all trial activity followed by staggered reopening of sites due to variable COVID-19 activity and clinical priorities. Many clinical laboratories switched to algorithms that included free toxin assays in addition to polymerase chain reaction (PCR) tests out of concern for overdiagnosis based on PCR testing alone, reducing the number of potentially enrollable cases. There has been increased empirical vancomycin treatment for recurrent CDI without confirmation by stool testing, a requirement for enrollment, and a recruitment strategy for identifying potential cases. Finally, conflicting clinical guidelines for recurrent CDI has created potential equipoise when considering enrollment. Ongoing educational efforts have been made to clarify the protocol and emphasize the validity of the research question as well as protoco changes to allow safe enrollment and follow-up of participants in the face of the ongoing COVID-19 pandemic. The CSP 2005/VALOR is a phase III randomized, open label, multicenter clinical trial of Veteran patients with operable stage I non-small cell lung cancer that compares stereotactic radiotherapy and anatomic pulmonary resection with a primary outcome measure of overall survival. The study was activated in 2017 and recruitment to the trial has been affected by ongoing changes in public and clinician perceptions about stereotactic radiotherapy and surgery that have interfered with equipoise and willingness of participants to enroll. The study team perpetually addresses this challenge through group conversations with local site investigators, study coordinators, and other research personnel to preserve group equipoise across the study. Since the study's activation, new safety information about stereotactic radiotherapy has emerged necessitating protocol modifications while aiming to preserve internal and external validity. The includes modifying standard operating procedures for the study's centralized quality assurance program that has had to adapt its process to remain contemporary. STARPORT, funded by VA CSRD with CSP collaboration, is a randomized, open label, multicenter clinical trial of Veteran patients with oligorecurrent prostate cancer comparing the effects of standard systemic therapy (SST) alone or with PET-directed local therapy using surgery or radiation. Although enrollment was initiated in 2021, changes are already evident in clinical practice guidelines regarding the use of imaging in workup in this patient population. Shortly before the start of accrual, 18F-DCFPyL PSMA PET/CT received FDA-approval. Consequently, it is being rapidly adopted at the STARPORT VA medical centers and the use of conventional imaging using CT or bone scan prior to PET/CT imaging-part of the original eligibility criteria-quickly is falling out of favor. Furthermore, shortly after the start of enrollment, NCCN guidelines adopted the stance that conventional imaging was no longer required in the setting of PSMA PET/CT imaging, solidifying the transition away from conventional imaging. Thus, the protocol is being amended to remove the requirement for conventional imaging as part of workup for oligorecurrence. In addition, to be generalizable, the study is designed to integrate future PSMA radiotracers that are incorporated into practice as well as changes in SST regimens over the time of the study.

The evolving landscape of pulmonary arterial hypertension clinical trials

Although it is a rare disease, the number of available therapeutic options for treating pulmonary arterial hypertension has increased since the late 1990s, with multiple drugs developed that are shown to be effective in phase 3 randomised controlled trials. Despite considerable advancements in pulmonary arterial hypertension treatment, prognosis remains poor. Existing therapies target pulmonary endothelial dysfunction with vasodilation and anti-proliferative effects. Novel therapies that target proliferative vascular remodelling and affect important outcomes are urgently needed. There is need for additional innovations in clinical trial design so that all emerging candidate therapies can be rigorously studied. Pulmonary arterial hypertension trial design has shifted from short-term submaximal exercise capacity as a primary endpoint, to larger clinical event-driven trial outcomes. Event-driven pulmonary arterial hypertension trials could face feasibility and efficiency issues in the future because increasing sample sizes and longer follow-up durations are needed, which would be problematic in such a rare disease. Enrichment strategies, innovative and alternative trial designs, and novel trial endpoints are potential solutions that could improve the efficiency of future pulmonary arterial hypertension trials while maintaining robustness and clinically meaningful evidence.Copyright © 2022 Elsevier Ltd

Optimizing Precision Medicine Cancer Clinical Trials

With the advent of precision medicine, getting the right treatment for the right patient at the right time has illuminated a variety of challenges and opportunities for innovation in trial design and conduct. Although there is no onesize- fits-all approach to precision medicine, a number of approaches, particularly basket and umbrella trial platforms that permit simultaneous evaluation of multiple treatments in multiple patient cohorts, have evolved to improve trial efficiency. The novel coronavirus pandemic has illuminated the need for, and feasibility of, conducting trials with fewer requirements, greater flexibility, and more decentralization. Through the lens of precision medicine cancer clinical trials, successes and challenges will be discussed to share practical solutions of how to improve evidence generation in the era of precision medicine. Through discussion of precision medicine cancer clinical trials within the United States, this session will provide an overview of how best to optimize these clinical trials. This session comprises the following three main topic areas: matching treatments to patients, including the use of novel patient identification strategies, genomic matching rules, molecular tumor boards (MTBs), decision-support tools, incorporating precision medicine trials into a research portfolio, and how to overcome challenges;accelerating evidence development, including the use of adaptive trial designs, cohort management strategies and data sharing plans;and improving diversity of trial participants and increasing generalizability of study results through expanded eligibility criteria and site selection strategies. This topic will be explored through 90 min of invited talks and a panel discussion with Q&A. Moderator and session chair, Richard L Schilsky, MD, FACP, FSCT, FASCO, will introduce the session and speakers and provide an introduction on the basics of precision oncology. Timothy Cannon, MD, a medical oncologist and clinical trial researcher, will present a case study of two patients with the same alteration and discuss how the care for each differed based on access to a precision medicine cancer clinical trial. Dr. Cannon will also discuss how to implement precision medicine trials within a research portfolio and how to identify patients at a site. Christine Walko, PharmD, BCOP, FCCP, a pharmacist and researcher, will then discuss the basics of matching therapies to genomics, how to use decision support tools, the role of an MTB, and identifying therapeutic options for patients. Edward S Kim, MD, MBA, FACP, FASCO, a medical oncologist, will talk about MTBs from a clinician perspective and precision medicine cancer clinical trials from a community practice perspective. Dr. Kim will also speak about how to extend the research team to create an adequate community research portfolio and about using broader eligibility criteria that might facilitate enrollment of diverse populations. Jane Perlmutter, PhD, MBA, FASCO, a cancer survivor and patient advocate, will discuss what pragmatic trials are, how they increase the opportunity for diversity and generalizability, and patient perspectives regarding pragmatic and precision cancer clinical trials. Susan Halabi, PhD, FASCO, FSCT, a researcher and professor of biostatistics and bioinformatics, will talk about the best ways to design an adaptive trial, especially its role in real-world settings, how these types of designs can be used for efficient signal finding in rare populations, and how these trials can create opportunities for data sharing and collaboration. Pam K Mangat, MS, a research scientist and the Director of Clinical Research for American Society of Clinical Oncology's (ASCO) Targeted Agent and Profiling Utilization Registry (TAPUR) Study, will discuss the operations behind a precision medicine study, advantages and disadvantages of a pragmatic trial, cohort closing and collapsing rules to help with management of large numbers of small cohorts, and contributing knowledge to other trials. The session will conclude with a panel di cussion moderated by session chair, Richard L Schilsky, MD, FACP, FSCT, FASCO, for approximately 10 min, with 5 min for a Q&A session.

The relationship between pragmatism, timing, and study size on impact of randomized trials: a qualitative, hypothesis generating study of trials of systemic corticosteroids for COVID-19.

OBJECTIVE: To explore qualitatively the relationship between selected trial design choices and proxies for a scientific and clinical uptake in a cohort of published randomized controlled trials (RCTs) of corticosteroids for COVID-19, to identify design characteristics that may result in trials with potential to eliminate equipoise, achieve uptake, and help reduce research waste. STUDY DESIGN AND SETTING: A systematic literature search and qualitative, narrative review of published RCTs (up to April 13, 2021) evaluating the effectiveness of systemic corticosteroids in treatment of COVID-19. We extracted information on sample size, number of centers, single-country or multi-country conduct, dates of initiation and of publication, risk of bias and pragmatism scores, and also on an impact measured by citation in scientific literature and in clinical guidelines. We qualitatively compared design features of the highest impact vs. other trials. RESULTS: Randomised Evaluation of COVID-19 Therapy (RECOVERY) was by the most impactful of the seven eligible RCTs as it was 10 times more frequently cited in peer-reviewed literature and influenced all the selected COVID-19 treatment guidelines. All trials started recruiting from similar dates. RECOVERY was a single-country, multicentre platform trial at low risk of bias, features which also fail to distinguish it from the other trials. RECOVERY was distinguished by more strongly pragmatic design features, more centers, and more rapid recruitment resulting in a larger sample size and early publication. CONCLUSION: Higher pragmatism scores may contribute to recruiting more centers and more rapid recruitment of patients at each center, leading to larger size, earlier publication, and greater scientific and guideline uptake. By eliminating equipoise, RECOVERY rendered other simultaneous trials redundant. Further work is needed to confirm these findings in a larger quantitative study and to identify the individual contribution of each characteristic of pragmatism to conduct and impact of trials and their interaction in different national contexts. Until then, research waste might be reduced by designing trials with as many of the characteristics of RECOVERY as is feasible.

Effectiveness of Mental Health Apps for Distress During COVID-19 in US Unemployed and Essential Workers: Remote Pragmatic Randomized Clinical Trial.

BACKGROUND: During the COVID-19 pandemic, the general public was concerned about the mental health impacts of unemployment due to COVID-19 and the stress essential workers experienced during this time. Several reports indicated that people in distress were turning to digital technology, but there was little evidence about the impact of these tools on mitigating distress. OBJECTIVE: This study seeks to determine the acceptability, feasibility, usability, and effectiveness of mobile mental health apps for decreasing mental health symptoms in essential workers and unemployed individuals with suicide risk. METHODS: We recruited participants who indicated that they were unemployed because of COVID-19 or were COVID-19-designated essential workers. Participants were randomized to 1 of 4 free commercial mobile apps for managing distress that were (1) highly rated by PsyberGuide and (2) met the criteria for intervention features these participants indicated were desirable in a previous survey. Participants used the apps for 4 weeks and completed baseline and 4-week self-assessments of depression, anxiety emotional regulation, and suicide risk. RESULTS: We found no differences between the apps in any outcome but did find significant changes in depression and anxiety over time (Patient Health Questionnaire [PHQ]-9: estimate=-1.5, SE 0.2, 95% CI -1.1 to -1.8, P<.001; Generalized Anxiety Disorder Scale [GAD]-7: estimate=-1.3, SE 0.2, 95% CI -1.0 to -1.6, P<.001). We found no significant changes in suicidal behavior (Suicide Behaviors Questionnaire-Revised [SBQ-R]) or emotional regulation (Difficulties in Emotion Regulation Scale - Short Form [DERS-SF]) for the 4 weeks. We did find a significant dose-response pattern for changes in depression and anxiety. Using the app at least once a week resulted in greater improvements in treatment conditions over time on depression (estimate=-0.6, SE 0.2, 95% CI 1.0-0.2, P=.003) and anxiety (estimate=0.1, SE 0.2, 95% CI 0.4-0.6, P=.78). There was no association between app frequency and changes in suicidal behavior (SBQ-R) or emotional regulation (DERS-SF). We further found a significant difference between the conditions with regard to app usability, with the control app being the most usable (meanBeautiful Mood 72.9, SD 16.7; meanCOVID Coach 71.2, SD 15.4; meanCalm 66.8, SD 17.3; mean7 Cups 65.2, SD 17.7). We found no significant differences for app acceptability or appropriateness. CONCLUSIONS: Few studies have evaluated prospectively the utility and usability of commercial apps for mood. This study found that free, self-guided commercial mobile mental health apps are seen as usable, but no one app is superior to the other. Although we found that regular use is indicated for effects on depression and anxiety to occur in those who are more symptomatic, regression to the mean cannot be ruled out. TRIAL REGISTRATION: ClinicalTrials.gov NCT04536935; https://tinyurl.com/mr36zx3s.

Change in breast cancer risk perception related to perceived COVID-19 risk: A WISDOM sub-population analysis

Background: Obstacles to access to care due to the perceptions of the risk posed by COVID-19 have led to unprecedented disruptions in cancer care. Yet, little is understood about whether perceived COVID- 19 risk influences perceptions of cancer risk. We examined how COVID-19 risk perception was associated with perceptions of breast cancer risk over one year of the pandemic among women enrolled in the WISDOM study, a PCORI-funded pragmatic trial testing risk-based cancer screening that began before the pandemic. Methods: We conducted four longitudinal surveys among the 13,002 women enrolled in the WISDOM study from May - December 2020. Responses from 8,285 women are eligible for inclusion in this analysis leading to a total sample size of 16,859 survey responses. Surveys were conducted online and asked women's perceived lifetime chance of developing breast cancer (0- 100%). COVID-19 risk perception was reported on a 5-point scale from Very Low to Very High. We computed the difference between breast cancer risk perception at each COVID-19 survey to pre-COVID breast cancer risk perception, measured as a secondary aim of the WISDOM study, and compared that to COVID-19 risk perception at each time point. Results: Across the four survey waves, most women perceived low COVID risk: 29% very low, 42% moderately low, 23% neither high nor low and 6% high or very high. Overall, breast cancer risk perception declined for those with very low COVID-19 risk perception and rose for women in the highest levels of COVID-19 risk perception. However, changes in breast cancer risk perception associated with COVID risk perception were small. For example, in survey wave 4, breast cancer risk change was -2.4% very low, -1.4% low, 2.5% not high or low and 3.1% high or very high. (Table). Conclusions: Among women participating in a pragmatic trial testing riskbased cancer screening, COVID risk perception had a small relationship with change in breast cancer risk perception. Change in breast cancer risk perception paralleled COVID-19 risk perception. This calls for exploration of the underpinnings of these risk changes and may have implications for changes in cancer screening behavior related to COVID-19.

Whole Health Options in Pain Education (wHOPE): A Multi-Site Pragmatic Trial of a VA Whole Health Team Approach to Pain Management in Veterans

Methods: Target enrollment in the wHOPE (Whole Health Options in Pain Education) trial is 750 veterans with moderate to severe chronic pain from five geographically diverse VA facilities across the U.S. We are creating an inclusive and generalizable sample through few exclusion criteria, over-sampling and stratified randomization, prioritizing women veterans and those prescribed opioids, while closely monitoring racial and ethnic diversity. The primary aim of the trial is to determine whether a Whole Health Team (WHT) (interdisciplinary Whole Health/integrative pain team) is superior to Primary Care Group Education (PC-GE, abbreviated group Cognitive Behavioral Therapy for Chronic Pain), and whether both are superior to Usual Primary Care (UPC) in decreasing pain interference and secondarily, in improving quality of life and use of non-pharmacological modalities to manage chronic pain. An implementation evaluation and budget impact analysis will provide information about feasibility, maintenance, and sustainability. Descriptive statistics characterized wHOPE study participants including COVID-19-related impacts. Results: To date, of 248 randomized participants, mean age is 60.2 (SD+/-12.3) years;39% women;23% Black or African American and 9.2% Hispanic/Latinx;27% were prescribed opioids. Roughly half endorsed moderate to severe depression, moderate PTSD symptoms, and 58% reported sleep difficulties. Roughly 20% engaged in hazardous drinking and 10% problem drug use. At baseline, veterans reported high rates of non-pharmacological and CIH pain management, e.g., mindfulness (42%);spinal manipulation (32%). As a result of COVID, wHOPE participants reported worsening: mental and emotional health (73%);access to healthcare (59%);pain intensity (48%) and use of tobacco (44%) and cannabis products (36%). Background: To conduct a pragmatic trial to establish evidence for the VA Whole Health model for chronic pain care. Conclusion: This ongoing multi-site pragmatic trial in a diverse group of veterans with chronic pain and high rates of comorbidity indicates high baseline use of CIH and substantial negative COVID-related impacts.

COVID Impacts on Pragmatic Trials of Nonpharmacological Approaches to Pain Management: A Mixed Methods Evaluation

Methods: This 2-phase study used a sequential, mixed methods design to explore changes made to study protocols, particularly clinical interventions, in response to the evolving pandemic. A structured REDCap questionnaire queried about emerging adaptations using the periodic reflections method across 3 timepoints. Following Phase 1 analysis, brief checklists and 3 setting-specific focus groups were completed with principal investigators and key staff via video-conference to elicit information about study adaptations. Focus group interview schedules and directed content analyses were guided by the Framework for Reporting Adaptations and Modifications-Expanded (FRAME) taxonomy. Results: Eleven PCTs completed questionnaires and 16 representatives from 10 PCTs joined focus groups. In periodic reflections, teams reported between 2 to 6 adaptations in the first 5 months of the pandemic. PCTs in the implementation stage reported delays in site/clinic onboarding, staff training, and/or patient recruitment, with 3 trials pausing intervention delivery. Intervention protocols were adapted with 6 PCTs adding/expanding virtual care. Trials testing manual therapies reported clinic closures and care restrictions. FRAME analyses of focus groups identified adaptation goals to increase trial feasibility, decrease patient/provider COVID exposures, and increasing patient engagement/retention. Context adaptations focused on virtual delivery while content adaptations included adding elements to enhance safety, tailoring/refining protocols for virtual delivery, and removing/skipping hands-on pain management interventions. Background: The COVID-19 pandemic changed the delivery of healthcare services and disrupted clinical research programs. This study evaluated adaptations made to 11 in-progress, pragmatic clinical trials (PCTs) of non-pharmacological pain management interventions in Department of Veterans Affairs and Department of Defense healthcare facilities. Conclusion: While core elements of trial interventions were retained, investigators were required to adapt study protocols for non-pharmacological pain management PCTs to address COVID-related disruptions and restrictions.

Physical Therapist Training Challenges for an Embedded Pragmatic Trial: Fibromyalgia TENS in Physical Therapy Study

Transcutaneous electrical nerve stimulation (TENS), a non-pharmacological treatment, is safe and effective for movement-evoked pain in individuals with Fibromyalgia (FM). The purpose of our NIH-funded pragmatic clinical trial, Fibromyalgia TENS in PT Study (FM-TIPS), assesses feasibility and effectiveness of adding TENS to usual physical therapy (PT) treatment in individuals with FM. We partnered with 33 sites in 6 healthcare systems, training 150+ Midwest clinicians. Outpatient PT clinic sites are cluster randomized to a TENS or a No-TENS intervention, stratified by system and clinic size. We will recruit ∼600 patients with a primary or secondary diagnosis of FM. We developed comprehensive communication and training procedures to ensure study fidelity and adapted over the course of the study to enhance learning. We will provide an overview and the impact of the pandemic on these procedures. Representatives for each healthcare system, each clinic and the study team were identified for communication and training. Training included initial study introduction, human subjects protection, and study procedures. We used a hybrid approach with written, video, onsite, and virtual instruction. All materials and procedures, for clinician and patient-facing materials, website, videos, equipment use (iPad for screening, TENS units), and clinician procedures for PT visits 1-3, were piloted and reviewed by clinicians from each healthcare system. Additional communication and feedback include weekly enrollment reports, monthly newsletters, relationship building with clinicians, enrollment incentives, and continuing education webinars. The pandemic required creative and evolving solutions to maintain study involvement and recruitment. Barriers for enrollment are screening PT Visit 1, comfort level of clinicians for PT Visits 2 and 3, delays/alterations in training and planning, clinician demands, clinicians/patient illness, and staff shortages in the clinics. Current enrollment, study training and implementation has been affected by COVID-19 and we developed creative methods for training and implementation for FM-TIPS. Grant support from Research supported in this USASP was supported by National Institutes of Health Heal Initiative Grant UG3/UH3 AR076387-01 and UL1TR002537.

Facilitators and Barriers to Implementation of a Transcutaneous Electrical Nerve Stimulation Intervention in a Pragmatic Clinical Trial

Fibromyalgia TENS in Physical Therapy (PT) Study (FM-TIPS) is testing feasibility and efficacy of Transcutaneous Electrical Nerve Stimulation (TENS). We present our experience for implementing TENS into PT clinics and virtual training to participants on TENS in a pragmatic clinical. FM-TIPS is a pragmatic, cluster-randomized clinical trial examining if the addition of TENS to routine PT improves movement-evoked pain in fibromyalgia (FM). FM patients (n=600) will be enrolled from 35 PT clinics across six Midwest healthcare systems into either a TENS or no-TENS group. All subjects randomized by TENS clinics receive TENS starting on Day 1. The no-TENS clinics start after completion of the primary outcome on Day 60. In the TENS group, Physical therapists (PTs) provide TENS education in person, while in the no-TENS group, study staff provide TENS education virtually. To facilitate implementation, we selected a study-specific TENS unit that provides mixed frequency TENS with intensity as the only adjustable parameter. All PTs were trained in proper use of the TENS unit in-person. While most PTs embraced the addition of TENS, some had not used TENS and had difficulty adapting practice to include TENS. For virtual visits in the no-TENS group, a standardized procedure was developed and completed by study staff PTs. TENS units were shipped to subject's and zoom visits were scheduled at the subject's convenience within a 10-day window. Most subjects completed virtual TENS training and implementation without difficulties. Technology limitations provided a significant barrier for some subjects. Most clinics have adopted and incorporated TENS intervention. Implementing virtual TENS training in a pragmatic trial can be successful for participant intervention. Due to the current COVID-19 pandemic, participants are more aware of the need to complete interventions via virtual mechanisms. Barriers to virtual TENS instruction are often due to internet and device limitations. FM-TIPS work is supported by the National Institutes of Health (NIH) through the NIH HEAL Initiative under award number UG3AR076387 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. This work also received logistical and technical support from the PRISM Resource Coordinating Center under award number U24AT010961 from the NIH through the NIH HEAL Initiative. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or its HEAL Initiative.

Effect of home-based smartphone-supported high-intensity interval training on cardiorespiratory fitness in breast cancer survivors: A randomized controlled trial of the habit-B program

Background: A strategy for maintaining and/or improving cardiorespiratory fitness (CRF) in the growing population of cancer survivors is of major clinical importance in the COVID-19 era. With the aim of increasing CRF, recent studies have focused on the use of high-intensity interval training (HIIT) in supervised experimental settings, which appeared to be more beneficial than usual care in cancer survivors at all stages of treatment and aftercare. However, the effect of unsupervised HIIT on increasing CRF in breast cancer survivors is not known. Purpose: To determine whether the newly developed habit-B program, which involves home-based smartphone-supported HIIT using body-weight exercises, improves CRF in early-stage breast cancer survivors. We hypothesized that the habit-B program would improve VO2peak compared with a control group. Methods: This single-center, 12-week, parallel-group, single-blind, randomized controlled trial involved 50 women with stage I-IIa breast cancer, aged 20 to 59 years, who had completed initial treatment except for hormone therapy. Participants wore a smartwatch and were randomized to either the exercise or control group from May 27, 2019 through November 30, 2020. The planned sample size was 60 Spatients to detect the increase of 2.0 ml/kg/min change in VO2peak with a standard deviation of 2.6 ml/kg/min, one-sided significance level of 2.5% and 80% power. The exercise group underwent home-based HIIT using a smartphone and a Fitbit Versa thrice weekly for 12 weeks (three times per week). The primary outcome was the 12-week change in peak oxygen uptake (VO2peak;mL/kg/min) between the groups. Other outcomes included muscle strength, 6-min walk test, resting heart rate, physical activity, fatigue, safety, and quality of life. Results: Of the 50 participants, 44 (exercise group, n=23;control group, n=21) completed the CRF assessment and 6 did not because of issues related to the COVID-19 pandemic. The change in VO2peak increased significantly in the exercise group (0.9 [95%CI, 0.1 to 1.7]) compared with the control group (-0.8 [95%CI,-1.5 to-0.1]) (mean difference, 1.7 [95% CI, 0.7 to 2.7], p <.01). Leg strength also increased significantly in the exercise group compared with the control group (mean difference, 13.5 [95% CI, 2.9 to 24.1], p <.01). Changes in other outcomes were not significantly different between the groups. Conclusion: A home-based HIIT intervention can lead to improved cardiorespiratory fitness and muscle strength in early-stage breast cancer survivors;however, a multicenter pragmatic clinical trial is required to confirm the benefits of the habit-B program.

A randomized, pragmatic trial investigating the timing of radiotherapy and endocrine in patients with early stage breast cancer (REaCT-RETT trial)

The optimal timing of commencing adjuvant endocrine therapy (ET) relative to adjuvant radiotherapy (RT) (i.e. concurrent with or sequential to radiotherapy) remains unknown. A systematic review performed by our team was unable to answer this question due to a lack of high quality, randomized data on concurrent versus sequential ET and RT. Surveys of physicians confirmed this uncertainty and highlighted theoretical concerns for increased side effects with concurrent treatment. Respondents showed keen interest in obtaining real world, randomized data to guide clinical practice. REaCT-RETT is a pragmatic, randomized, non-inferiority trial comparing concurrent and sequential ET and RT in early breast cancer (EBC). The primary endpoint will assess the change in ET side effects at baseline and 3 months post radiation, using the Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES), with primary analysis based on an analysis of covariance (ANCOVA). With a sample size of 176 patients (88 per arm), an ANCOVA would have 80% power (α=0.05) to detect effect sizes as small as 0.25 regardless of the correlation with covariates. It is hypothesized that concurrent therapy will be non-inferior to sequential therapy in terms of ET side effects. Secondary endpoints will examine RT toxicity, ET compliance, quality of S life, and cost-effectiveness. Patients with HR positive EBC planned to receive both adjuvant ET and RT were eligible. Patients who previously received ET for invasive breast cancer, or RT in the same breast, were excluded. The trial is conducted by The Ottawa Hospital's (TOH) innovative Rethinking Clinical Trials (REaCT) program (https://react.ohri.ca/) which strives to improve access to patient-centered, pragmatic clinical trials by removing barriers for patients and researchers. Integral features of the program include broad eligibility criteria, a verbal consent model, and pragmatic data collection and assessment procedures. REaCT is the largest pragmatic cancer clinical trials program in Canada, with over 3, 200 patients randomized in 18 clinical trials at 15 sites across Canada. REaCT-RETT accrued patients from September 2019 to January 2021. Data collection is ongoing, with final patient follow up expected April 2022. The timing of accrual provided a unique opportunity to adapt in response to restrictions due to the COVID-19 pandemic, which began to impact trial sites in March 2020. The target sample size was met with 262 patients randomized (1:1) across 3 sites in Ontario, 98% from TOH. A mean of 19 patients/month were accrued prior to the pandemic, compared to a mean of 13 patients/month after March 2020. Twenty-two patients were removed due to withdrawal of consent, ineligibility, or physician choice, and the pandemic was not a significant contributing factor. Since March 2020 there have been 772 patient follow ups, of which 47% (364/772) have been virtual. Only 10% (102/1028) of trial mandated appointments have been missed to date. Compliance with baseline and 3-month FACT-ES questionnaires for the primary endpoint in evaluable patients was 90% (215/240) and 83% (198/240), respectively. The pandemic posed several challenges to the REaCT-RETT study including a decline in patient accrual, poor accrual at peripheral sites due to delayed opening, and a rapid switch to virtual patient care. However, the nimble REaCT methodology enabled virtual patient consent and data collection during the pandemic, allowing the trial to continue successfully, with final data expected for presentation summer 2022. Finally, despite the challenges of COVID-19 we have seen that patients and physicians remain interested in research, and we are applying valuable lessons learned to forthcoming REaCT trials to strengthen their performance during and beyond the ongoing pandemic.

Assessing the Implementation and Effectiveness of the Electronic Patient-Reported Outcome Tool for Older Adults With Complex Care Needs: Mixed Methods Study.

BACKGROUND: Goal-oriented care is being adopted to deliver person-centered primary care to older adults with multimorbidity and complex care needs. Although this model holds promise, its implementation remains a challenge. Digital health solutions may enable processes to improve adoption; however, they require evaluation to determine feasibility and impact. OBJECTIVE: This study aims to evaluate the implementation and effectiveness of the electronic Patient-Reported Outcome (ePRO) mobile app and portal system, designed to enable goal-oriented care delivery in interprofessional primary care practices. The research questions driving this study are as follows: Does ePRO improve quality of life and self-management in older adults with complex needs? What mechanisms are likely driving observed outcomes? METHODS: A multimethod, pragmatic randomized controlled trial using a stepped-wedge design and ethnographic case studies was conducted over a 15-month period in 6 comprehensive primary care practices across Ontario with a target enrollment of 176 patients. The 6 practices were randomized into either early (3-month control period; 12-month intervention) or late (6-month control period; 9-month intervention) groups. The primary outcome measure of interest was the Assessment of Quality of Life-4D (AQoL-4D). Data were collected at baseline and at 3 monthly intervals for the duration of the trial. Ethnographic data included observations and interviews with patients and providers at the midpoint and end of the intervention. Outcome data were analyzed using linear models conducted at the individual level, accounting for cluster effects at the practice level, and ethnographic data were analyzed using qualitative description and framework analysis methods. RESULTS: Recruitment challenges resulted in fewer sites and participants than expected; of the 176 target, only 142 (80.6%) patients were identified as eligible to participate because of lower-than-expected provider participation and fewer-than-expected patients willing to participate or perceived as ready to engage in goal-setting. Of the 142 patients approached, 45 (32%) participated. Patients set a variety of goals related to self-management, mental health, social health, and overall well-being. Owing to underpowering, the impact of ePRO on quality of life could not be definitively assessed; however, the intervention group, ePRO plus usual care (mean 15.28, SD 18.60) demonstrated a nonsignificant decrease in quality of life (t24=-1.20; P=.24) when compared with usual care only (mean 21.76, SD 2.17). The ethnographic data reveal a complex implementation process in which the meaningfulness (or coherence) of the technology to individuals' lives and work acted as a key driver of adoption and tool appraisal. CONCLUSIONS: This trial experienced many unexpected and significant implementation challenges related to recruitment and engagement. Future studies could be improved through better alignment of the research methods and intervention to the complex and diverse clinical settings, dynamic goal-oriented care process, and readiness of provider and patient participants. TRIAL REGISTRATION: ClinicalTrials.gov NCT02917954; https://clinicaltrials.gov/ct2/show/NCT02917954.

Ptxrx study: How pragmatic trial design can inoculate against risks to study integrity in a global pandemic

Important safety measures limiting in-person contact to curb COVID-19 transmission make it more difficult for patients to access clinical trials and for sponsors to conduct trial management. These measures may lead to pausing or delaying study activities, to the determent of study participants and the study's integrity. The COVID-19 pandemic highlights the importance of efficient, innovative clinical trials designed with the capacity to be rapidly responsive to unique challenges. The US Department of Veterans Affairs Pentoxifylline in Diabetic Kidney Disease study is a multi-site, pragmatically designed randomized controlled trial that tests the hypothesis that pentoxifylline, when added to standard of care, leads to a reduction in the incidence of End Stage Renal Disease and mortality. The study opened for recruitment at six Veterans Affairs medical centers in December 2019, months before the COVID-19 pandemic disrupted all aspects of clinical care and halted all non-essential, in-person research activities. The study's protocol was designed to accommodate either in-person or remote participant follow-up and data collection for all visits after baseline. In addition, participant study visit schedules were built with the flexibility to align with existing clinic visits. The ability to collect data remotely resulted in a minimal amount of missing data. The study's investigational product is maintained and distributed centrally by the Albuquerque Cooperative Studies Program Pharmacy Center. This allowed for the continuation of distribution of the study investigational product without the need for an in-person visit to a Veterans Affairs medical center. Pentoxifylline in Diabetic Kidney Disease's trial design and protocol leverage the Veterans Affairs's research infrastructure, remote platforms, and a centralized mail-order pharmacy, and allowed the study to safely continue during a uniquely challenging global pandemic.

Impact of the COVID-19 pandemic on the design, operations, and analysis plans of dementiatrials

Multi-center randomized clinical trials in dementia research, especially in the stages aimed at primary and secondary prevention, have design characteristics that are particularly susceptible to the disruption caused by the COVID-19 pandemic, as well as the impact of COVID-19 illness on older adults. In this session, we will present the impact of the pandemic on design and analytical issues related to the choice of study population, trial design, clinical endpoints, and methods of outcome ascertainment. We will also discuss operational complexities and approaches to address or evaluate the impact of this global pandemic. This session will consist of three invited talks and a discussant. Each talk, representing clinical trials with different study designs, will be given by a member of the trial's statistical leadership team. The studies to be discussed are as follows: • Pharmacological Trials-The Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study: This is ongoing double-blind, placebocontrolled 240-week Phase 3 trial of an anti- Amyloid monoclonal antibody in older individuals (ages = 65-85 years) who have normal cognition and memory function but who may be at risk for memory loss due to Alzheimer's disease. This study completed enrollment in December 2017 and is anticipated to be completed in 2022. The primary outcome in the study is the Preclinical Alzheimer Cognitive Composite, with the Cognitive Function Index as a key secondary outcome. It is conducted as a public-private partnership between the National Institute on Aging and Eli Lilly. • Non-Pharmacological Trials-The US Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (US POINTER): This is an ongoing 2-year clinical trial, that began recruiting in May 2019, to evaluate whether lifestyle interventions that simultaneously target many risk factors protect cognitive function in older adults (ages 60-79 years) who are at increased risk for cognitive decline. The primary outcome of this study is a global cognitive composite score. It is funded by the Alzheimer's Association. • Pragmatic Trials-The Pragmatic Evaluation of Events and Benefits of Lipid-Lowering in Older Adults (PREVENTABLE): This is a pragmatic trial that began recruitment in September 2020, studying the effectiveness of statins in adults 75 years or older without known cardiovascular disease on a primary outcome of survival free of dementia and disability. It is funded by the National Institute on Aging and the National Heart, Lung, and Blood Institute. While the talks in the session will describe the experiences and decisions of the individual study team, the discussant will compare and contrast these experiences across the types of designs and stage of study. Speakers: Michael Donohue, PhD, Mark Espeland, PhD, and Nicholas Pajewski, PhD. Discussant: Rema Raman, PhD, University of Southern California.