Clinical trial facilitators: A novel approach to support the execution of clinical research at the study site level.

In the summer of 2020, multiple efforts were undertaken to establish safe and effective vaccines to combat the spread of the coronavirus disease (COVID-19). In the United States (U.S.), Operation Warp Speed (OWS) was the program designated to coordinate such efforts. OWS was a partnership between the Department of Health and Human Services (HHS), the Department of Defense (DOD), and the private sector, that aimed to help accelerate control of the COVID-19 pandemic by advancing development, manufacturing, and distribution of vaccines, therapeutics, and diagnostics. The U.S. Department of Veterans Affairs' (VA) was identified as a potential collaborator in several large-scale OWS Phase III clinical trial efforts designed to evaluate the safety and efficacy of various vaccines that were in development. Given the global importance of these trials, it was recognized that there would be a need for a coordinated, centralized effort within VA to ensure that its medical centers (sites) would be ready and able to efficiently initiate, recruit, and enroll into these trials. The manuscript outlines the partnership and start-up activities led by two key divisions of the VA's Office of Research and Development's clinical research enterprise. These efforts focused on site and enterprise-level requirements for multiple trials, with one trial serving as the most prominently featured of these studies within the VA. As a result, several best practices arose that included designating clinical trial facilitators to study sites to support study initiation activities and successful study enrollment at these locations in an efficient and timely fashion.

Development and implementation of standardized study performance metrics for a VA healthcare system clinical research consortium.

The cost of conducting clinical trials is continuously increasing and is driven in large part by the time and resources required to activate trials and reach accrual targets. The impact of low enrollment in a clinical trial can negatively affect the validity of study results and delay its generalizability to the broader population. Quality is a multidimensional concept which could relate to the design, conduct, and analysis of a trial, its clinical relevance, protection/safety of study participants, or quality of reporting. Furthermore, the quality of controlled trials is of obvious relevance to systematic reviews and if the "raw material" or "data" is flawed then the conclusions of systematic reviews cannot be trusted. To date, the literature surrounding the establishment of standardized study enrollment and quality metrics to assess site performance in clinical trial consortiums is scarce. The lack of these metrics presents challenges to study site teams, sponsors, and other clinical research enterprise key stakeholders for adequately monitoring and evaluating study site performance as it relates to fulfilling trial enrollment and quality goals. The Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) Network of Dedicated Enrollment Sites (NODES) undertook an effort to determine the feasibility of establishing and implementing standardized study enrollment and quality metrics for a clinical research consortium (NODES) as a tool to evaluate its performance. In this manuscript, we describe the development and implementation of standardized study enrollment and quality metrics to assess site performance across studies in our clinical research consortium.

Increasing access to clinical research using an innovative mobile recruitment approach: The (MoRe) concept.

BACKGROUND: Access to healthcare delivery programs and systems is a primary correlate to the overall health and well-being of Veterans and the general population. Participation in clinical research is a gateway to novel therapies that are intended to address current global health issues. Meeting or exceeding recruitment goals in clinical research is one of the key determinants of the timely and successful completion of a study. The travel and time burdens experienced by study participants are often considered barriers to their enrollment into clinical research. The Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) established a consortium of nine VA medical centers (VAMCs) called the Network of Dedicated Enrollment Sites (NODES). The NODES program provides study site-level expertise and innovative approaches that address challenges to clinical research execution. In alignment with our mission, our program developed an approach to increase study participant access to clinical research through implementing "Mobile Recruitment (MoRe)" units. This manuscript describes the utility and challenges associated with employing this strategy to address three common barriers to clinical research participation: 1) research participant travel burden, 2) participant access to study opportunities, and 3) low participant enrollment. METHODS: A plan to introduce the Mobile Recruitment (MoRe) unit as a recruitment strategy was piloted for a high-volume, observational cohort study and mega biobank in the VA health care system, the "Million Veteran Program (MVP)". MoRe is a recruitment strategy for CSP research integrating mobile technology and atypical research recruitment locations. Recruitment locations include primary or main VA hospitals and their assigned VA Community-Based Outpatient Clinics (CBOCs). Each Node site (n = 9) received components of the MoRe unit including a laptop, printer, portable cart with storage space, cooler/ice packs for specimen storage and transport. Each site's usage of these components varied based on its respective needs. Activities focused on both VA main facilities and CBOC facilities for recruitment. RESULTS: Seven of the nine Node sites compared the effectiveness of the MoRe unit on MVP study enrollment outcomes over three-time points: pre-intervention period, intervention period, and post-intervention period. The utilization of MoRe in the intervention period demonstrated a 36.9% increase in enrollment compared to the previous six months (pre-intervention period). There was a 2% enrollment increase at the six-month post-intervention period as compared to the intervention period. When comparing the pre-intervention period to the post-intervention period (duration of eighteen months), enrollment increased by 38.9%. CONCLUSION: Five of the seven sites experienced an increase in enrollment during the intervention and post-intervention periods. The two sites without an increase in enrollment experienced various extenuating factors. Characteristics of sites using MoRe included the ability to utilize a smaller, unconventional space, i.e. not a traditional clinical research exam space for recruitment. MoRe was utilized in hospital laboratory space, CBOCs, primary care clinics, and other subspecialty clinics that allowed recruitment activities but did not have dedicated space to offer the research teams for that purpose. This initiative successfully demonstrated the benefit of deploying the unit, proving its utility in cases in where there was a lack of space or alternative workstations for research activities. The implementation of MoRe by NODES as a recruitment strategy for MVP may be transferable to other VA clinical research studies, as well as to other healthcare settings executing similar clinical research activities.

Individual Treatment of Posttraumatic Stress Disorder Using Mantram Repetition: A Randomized Clinical Trial.

OBJECTIVE: Previous studies suggest that group "mantram" (sacred word) repetition therapy, a non-trauma-focused complementary therapy for posttraumatic stress disorder (PTSD), may be an effective treatment for veterans. The authors compared individually delivered mantram repetition therapy and another non-trauma-focused treatment for PTSD. METHOD: The study was a two-site, open-allocation, blinded-assessment randomized trial involving 173 veterans diagnosed with military-related PTSD from two Veterans Affairs outpatient clinics (January 2012 to March 2014). The mantram group (N=89) learned skills for silent mantram repetition, slowing thoughts, and one-pointed attention. The comparison group (N=84) received present-centered therapy, focusing on currently stressful events and problem-solving skills. Both treatments were delivered individually in eight weekly 1-hour sessions. The primary outcome measure was change in PTSD symptom severity, as measured by the Clinician-Administered PTSD Scale (CAPS) and by self-report. Secondary outcome measures included insomnia, depression, anger, spiritual well-being, mindfulness, and quality of life. Intent-to-treat analysis was conducted using linear mixed models. RESULTS: The mantram group had significantly greater improvements in CAPS score than the present-centered therapy group, both at the posttreatment assessment (between-group difference across time, -9.98, 95% CI=-3.63, -16.00; d=0.49) and at the 2-month follow-up (between-group difference, -9.34, 95% CI=-1.50, -17.18; d=0.46). Self-reported PTSD symptom severity was also lower in the mantram group compared with the present-centered therapy group at the posttreatment assessment, but there was no difference at the 2-month follow-up. Significantly more participants in the mantram group (59%) than in the present-centered therapy group (40%) who completed the 2-month follow-up no longer met criteria for PTSD (p<0.04). However, the percentage of participants in the mantram group (75%) compared with participants in the present-centered therapy group (61%) who experienced clinically meaningful changes (≥10-point improvements) in CAPS score did not differ significantly between groups. Reductions in insomnia were significantly greater for participants in the mantram group at both posttreatment assessment and 2-month follow-up. CONCLUSIONS: In a sample of veterans with PTSD, individually delivered mantram repetition therapy was generally more effective than present-centered therapy for reducing PTSD symptom severity and insomnia.

Research site mentoring: A novel approach to improving study recruitment.

BACKGROUND/AIMS: The VA Cooperative Studies Program's (CSP) Network of Dedicated Enrollment Sites (NODES) is a consortium of nine VA medical centers (VAMCs) with teams (nodes) dedicated to enhance performance, compliance, and management of CSP multi-site clinical trials. The West Haven CSP Coordinating Center (WH-CSPCC), study coordinating center for CSP #577, Colonoscopy Versus Fecal Immunochemical Test (FIT) in Reducing Mortality from Colorectal Cancer (CONFIRM) trial, and NODES piloted a "site mentoring" (hub-and-spoke) model. In this model, a node site would work one-on-one with a low enrolling CONFIRM site to identify and overcome barriers to recruitment. The aim was to determine the impact of a research site mentoring model on study recruitment and examine site-level characteristics that facilitate or impede it. RESULTS: Sites in the mentorship pilot had an average improvement of 5 ±â€¯4 participants randomized per month (min -2.6; max 11.6; SD 4.3). Four of ten sites (40%) demonstrated continuous improvement in the average number of randomized participants per month after the pilot intervention and at three-month follow-up (post-intervention), as compared to the five-month period preceding the intervention. An additional two sites (20%) demonstrated improvement in the average number of randomized participants per month after the pilot intervention, and sustained that level of improvement at three-month follow-up (post-intervention). Additionally, six of ten sites (60%) demonstrated an increased number of participants screened for eligibility immediately following the intervention and at three-month follow-up (post-intervention). Only one site showed a decreased monthly average of randomized participants shortly after the intervention and through the three-month follow-up period. CONCLUSIONS: The site mentoring model was successful in improving recruitment at low enrolling CONFIRM sites. An additional feasibility assessment is needed to determine if this mentoring model will be effective with other CSP trials.

Efficacy of the Mantram Repetition Program for Insomnia in Veterans With Posttraumatic Stress Disorder: A Naturalistic Study.

Statistics show that more than 80% of Veterans mention posttraumatic stress disorder (PTSD)-related symptoms when seeking treatment. Sleep disturbances and nightmares are among the top 3 presenting problems. Current PTSD trauma-focused therapies generally do not improve sleep disturbances. The mantram repetition program (MRP), a mind-body-spiritual intervention, teaches a portable set of cognitive-spiritual skills for symptom management. The aim of this study was to evaluate the efficacy of the MRP on insomnia in Veterans with PTSD in a naturalistic, clinical setting. Results show that participation in the MRP significantly reduced insomnia, as well as decreased self-reported and clinician-assessed PTSD symptom burden.

A cross-cutting approach to enhancing clinical trial site success: The Department of Veterans Affairs' Network of Dedicated Enrollment Sites (NODES) model.

BACKGROUND: Recruitment into clinical trials remains a key determinant to study completion and success. While various strategies have been proposed, it is unclear how they apply across different populations, diseases, and/or study goals. The ability to effectively overcome challenges may require different approaches that more broadly focus on addressing obstacles among sites that cannot be overcome by individual studies. METHODS: The Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) established the Network of Dedicated Enrollment Sites (NODES) as a consortium of sites to generate systematic site-level solutions to more efficiently recruit in CSP studies. Initial activities identified priorities and developed approaches through team-based efforts. Metrics were also developed to assess overall network performance. RESULTS: Network efforts produced several new strategies and best practices for common problems in CSP research. Recruitment strategies included bringing studies to patients and developing data programs using algorithms for finding eligible patients. Efficiency efforts focused on cross-training and standardizing performance reports. CONCLUSION: NODES addressed site challenges in clinical trial recruitment and management by taking an overall approach that looked at the system rather than individual studies. Practices and operational changes were implemented for CSP research related to recruitment, staff training and research methodology. The network activities suggest that team-based development of tools and insights may help better identify targets and increase efficiencies for clinical trials recruitment.

Chapter 5 mantram repetition: an evidence-based complementary practice for military personnel and veterans in the 21st century.

Today in the digital age, with our advances in modern technology and communication, there are additional stressors for our military personnel and Veterans. Constant dangers exist both on and off the battlefield, unlike prior wars that had clearly-defined war zones. In addition, medical advances have assisted in saving the lives of many more gravely injured troops than ever previously possible. As the wars in Iraq and Afghanistan come to an end, large numbers of service men and women are returning home with multiple injuries. This group of Veterans has significantly higher rates of posttraumatic stress disorder (PTSD) and traumatic brain injury than ever before reported. Although existing PTSD therapies have been found to be highly effective for many Veterans, there is a substantial minority unsatisfactorily treated. Mantram repetition, an innovative, complementary, evidence-based treatment, is proving to be successful for these new Veterans. When used regularly it helps with "road rage, impatience, anger, frustration, and being out of control." A mantram is a brief, sacred word or phrase that embodies divine power or the greatest positive energy one can imagine (Easwaran, 2008a). Mantram repetition is a simple, quick, personal, portable, and private complementary practice that may be used as an adjunct to current treatments for PTSD. Growing research evidence supports mantram repetition's value for dissemination and adoption in the 21st century. This chapter summarizes Mantram Program research conducted from 2003 to 2014. It describes the health-related benefits of the Mantram Program in various populations. The current research focuses on benefits for managing psychological distress and promoting quality of life in Veterans. Future areas for research are suggested.

Varicella zoster virus-specific immune responses to a herpes zoster vaccine in elderly recipients with major depression and the impact of antidepressant medications.

BACKGROUND: The Depression Substudy of the Shingles Prevention Study (SPS) was designed to evaluate the association between major depression and immune responses to a high-titer live attenuated varicella zoster virus (VZV) vaccine (zoster vaccine), which boosts cell-mediated immunity (CMI) to VZV and decreases the incidence and severity of herpes zoster (HZ). The Depression Substudy was a 2-year longitudinal cohort study in 92 community-dwelling adults≥60 years of age who were enrolled in the SPS, a large, double-blind, placebo-controlled Veterans Affairs Cooperative zoster vaccine efficacy study. METHODS: Forty subjects with major depressive disorder, stratified by use of antidepressant medications, and 52 age- and sex-matched controls with no history of depression or other mental illness had their VZV-CMI measured prior to vaccination with zoster vaccine or placebo and at 6 weeks, 1 year, and 2 years postvaccination. RESULTS: Depressed subjects who were not treated with antidepressant medications had lower levels of VZV-CMI following administration of zoster vaccine than nondepressed controls or depressed subjects receiving antidepressants even when antidepressant medications failed to alter depressive symptom severity (P<.005). Similar results were obtained taking into account the time-varying status of depression and use of antidepressant medications, as well as changes in depressive symptoms, during the postvaccination period. CONCLUSIONS: Depressed patients have diminished VZV-CMI responses to zoster vaccine, and treatment with antidepressant medication is associated with normalization of these responses. Because higher levels of VZV-CMI correlate with lower risk and severity of HZ, untreated depression may increase the risk and severity of HZ and reduce the efficacy of zoster vaccine.

Executive Function in Preschool Children: Test-Retest Reliability.

Research suggests that executive function (EF) may distinguish between children who are well- or ill-prepared for kindergarten, however, little is known about the test-retest reliability of measures of EF for children. We aimed to establish a battery of EF measures that are sensitive to both development and individual differences across the preschool period using Conflict and Delay subtests that had a cool (abstract) or hot (extrinsic reward) focus. Results from 151 children in three age groups (2.5, 3.5, and 4.5) suggested acceptable same-day test-retest reliability on all but Delay-Cool subtasks. These findings will inform appropriate measurement selection and development for future studies.

Major depressive disorder and immunity to varicella-zoster virus in the elderly.

Major depressive disorder has been associated with activation of inflammatory processes as well as with reductions in innate, adaptive and non-specific immune responses. The objective of this study was to evaluate the association between major depression and a disease-relevant immunologic response, namely varicella-zoster virus (VZV)-specific immunity, in elderly adults. A cross-sectional cohort study was conducted in 104 elderly community dwelling adults ≥ 60years of age who were enrolled in the depression substudy of the shingles prevention study, a double blind, placebo-controlled vaccine efficacy trial. Fifty-two subjects had a current major depressive disorder, and 52 age- and sex-matched controls had no history of depression or any mental illness. VZV-specific cell-mediated immunity (VZV-CMI) was measured by VZV responder cell frequency (VZV-RCF) and interferon-γ enzyme-linked immunospot (ELISPOT) assays, and antibody to VZV was measured by an enzyme-linked immunosorbent assay against affinity-purified VZV glycoproteins (gpELISA). VZV-CMI, measured by VZV-RCF, was significantly lower in the depressed group than in the controls (p<0.001), and VZV-RCF was inversely correlated with the severity of depressive symptoms in the depressed patients. In addition, an age-related reduction in VZV-RCF was observed in the depressed patients, but not in the controls. Furthermore, there was a trend for depressive symptom severity to be associated with lower ELISPOT counts. Finally, VZV-RCF was higher in depressed patients treated with antidepressant medications as compared to untreated depressed patients. Since lower levels of VZV-RCF appear to explain the increased risk and severity of herpes zoster observed in older adults, these findings suggest that, in addition to increasing age, depression may increase the risk and severity of herpes zoster.

Preschool children's performance in task switching on the dimensional change card sort task: separating the dimensions aids the ability to switch.

Fifty-seven children (53% female) at 3 ages (2 1/2, 3, and 3 1/2 years) were tested on the standard Dimensional Change Card Sort (DCCS) task with integrated stimuli (e.g., a red truck) and on a separated-dimensions version where colorless shapes were presented on a colored background (e.g., a black truck on a red background). Roughly twice as many children successfully switched sorting dimensions when color was a property of the background than when color was a property of the shape itself. Children succeeded 6 months earlier in switching sorting criteria when the dimensions were separated. When evidence of both indecision and accuracy was taken into account, a clear and rich developmental progression emerged. These results support an inhibitory control interpretation of preschoolers' problems on the DCCS task. Diamond theorized that young children can have difficulty integrating features not part of a single object and separating features of a single object so that the object can be categorized first by one attribute and then by another. Preschoolers remain stuck in thinking about objects according to the objects' initially relevant attribute (attentional inertia; Kirkham, Cruess, & Diamond, 2003). To switch perspectives, the old way of thinking about the objects must be inhibited. Separating color and shape reduced the need for such inhibition; a truck was always a truck, and the background was always red.