NIH-funded Clinical Trials Research Articles

Bridging the Gap: Culturally Responsive Strategies for NIH Trial Recruitment

Abstract Objective To enhance recruitment and participation rates of non-Hispanic Black (NHB) and Hispanic adult patients in a NIH-funded clinical trial studying an emerging health technology. Data Sources and Study Setting This study includes primary data collected in Los Angeles, California from November 2020 through November 2023. Study Design To improve the representation of NHB and Hispanic patients in a NIH-funded (NCT04409353) trial on virtual reality for chronic lower back pain (cLBP), we conducted a multi-phase study utilizing a mixed-method approach. First, we conducted focus groups with NHB and Hispanic cohorts aged 18 and older; based on the feedback, we culturally adapted recruitment materials and study correspondences concordantly. Additionally, a cohort builder was used to filter the electronic medical record to isolate non-Hispanic Black (NHB) and Hispanic patients with cLBP for micro-targeted recruitment. These changes were collectively integrated when the parent NIH study had recruited 222 of its 385 final samples (57.7%), creating a pre-post comparison timepoint (May 17, 2022). Quantitative analysis was performed to assess the efficacy of the modified recruitment strategies by comparing the number of recruited and randomized NHB and Hispanic patients pre- and post-intervention. Data Collection/Extraction Methods Semi-structured focus groups were conducted with NHB and Hispanic patients and community members (age 18 and older). The focus groups were conducted online and recorded with participant consent; transcripts of the recording underwent inductive thematic analysis. Emergent themes directed the modification of study materials, including revised language and imagery, targeted outreach, and incorporation of treating physicians, were implemented in the second half of the study. Quantitative analyses were conducted following parent study completion by comparing records added to the screening database following the implementation of new recruiting methods (5/17/2022) to those added before. Principal Findings Thematic analysis of focus groups identified four key themes: mistrust, lack of interest, culture, and communication. Modifications to recruitment methodology resulted in statistically significant increases in the pre- to post-randomization success rate for the overall study population (p < 0.001), the NHB population (p = 0.011), and the Hispanic population (p < 0.015). When looking at each cohort at different points in the recruitment process before and after the intervention, in the Hispanic population, we saw significant increases in the number approached (p < 0.001) and number randomized (p < 0.001) and statistically insignificant increases in the NHB population approached (p = 0.067) and randomized (p = 0.295). Similarly, we saw that the changes in the recruitment letter led to a statistically significant increase in Hispanic recruitment (7.0 to 39.1%, p < 0.001) but not the NHB cohort (19.6 to 35.8%, p < 0.065). Conclusion This study introduces several culturally sensitive considerations and possible approaches for the design of recruitment materials, addressing mistrust, lack of interest, culture, and communication for use in NHB and Hispanic populations. Similarly, the described microtargeting techniques leverage the technological advancements in cohort building to improve the reach and efficiency of the randomization rate of underrepresented groups thereby enhancing clinical trial diversity.

EXPLORATORY FACTOR ANALYSIS OF THE COMFORT ASSESSMENT IN DYING WITH DEMENTIA SCALE

Abstract The 14-item Comfort Assessment in Dying with Dementia (CAD-EOLD) scale is a widely used instrument measuring end-of-life care for people with dementia (PWD). The instrument has been used to evaluate symptom burden among PWD in nursing homes, but the measurement properties are less studied for symptoms reported by family and staff caregivers. We conducted an exploratory factor analysis to evaluate the psychometric properties of the scale using staff and family (N=476) responses to CAD-EOLD at the baseline of an NIH-funded clinical trial. Subjects were long-stay nursing home residents with moderate-to-severe cognitive impairment in Indiana and Maryland. Staff (n=368) and family members (n=108) completed the CAD-EOLD, describing participating residents. We performed separate exploratory factor analyses on family and staff responses. Family and staff data showed similar clustering patterns. Restlessness, anxiety, fear, crying, and moaning had high factor loadings in the first cluster, interpreted as “Physical and Psychological Distress” (loading range = 0.47–0.91). Choking, gurgling, and difficulty swallowing had high loadings in the second cluster that depicted “Dying Symptoms” (loading range = 0.62–1.15). Serenity, calm, and peace had high loadings in the third factor on “Well-Being” (loading range = 0.72–0.93). Three “Physical Distress” items (i.e., discomfort, pain, and shortness of breath) cross-loaded with “Dying Symptoms.” Accordingly, “Physical and Psychological Distress,” “Dying Symptoms,” and “Well-Being” represented important but separate dimensions for measuring end-of-life experiences of PWD. Findings demonstrated favorable construct validity of CAD-EOLD in PWD with moderate-to-severe cognitive impairment in nursing homes, as reported by staff and family caregivers.

Reporting and Representation of Participant Race and Ethnicity in National Institutes of Health–Funded Pediatric Clinical Trials

Enrolling racially and ethnically diverse pediatric research participants is critical to ensuring equitable access to health advances and generalizability of research findings. To examine the reporting of race and ethnicity for National Institutes of Health (NIH)-funded pediatric clinical trials and to assess the representation of pediatric participants from different racial and ethnic groups compared with distributions in the US population. This cross-sectional study included NIH-funded pediatric (ages 0-17 years) trials with grant funding completed between January 1, 2017, and December 31, 2019, and trial results reported as of June 30, 2022. National Institutes of Health policies and guidance statements on the reporting of race and ethnicity of participants in NIH-funded clinical trials. The main outcome was reporting of participant race and ethnicity for NIH-funded pediatric clinical trials in publications and ClinicalTrials.gov. There were 363 NIH-funded pediatric trials included in the analysis. Reporting of race and ethnicity data was similar in publications and ClinicalTrials.gov, with 90.3% (167 of 185) of publications and 93.9% (77 of 82) of ClinicalTrial.gov reports providing data on race and/or ethnicity. Among the 160 publications reporting race, there were 43 different race classifications, with only 3 publications (1.9%) using the NIH-required categories. By contrast, in ClinicalTrials.gov, 61 reports (79.2%) provided participant race and ethnicity using the NIH-specified categories (P < .001). There was racially and ethnically diverse enrollment of pediatric participants, with overrepresentation of racial and ethnic minority groups compared with the US population. This cross-sectional study of NIH-funded pediatric clinical trials found high rates of reporting of participant race and ethnicity, with diverse representation of trial participants. These findings suggest that the NIH is meeting its directive of ensuring diverse participant enrollment in the research it supports.

Using Simulation-Based Learning with Standardized Patients (SP) in an Implicit Bias Mitigation Clinician Training Program.

To describe the development and refinement of an implicit bias recognition and management training program for clinical trainees. In the context of an NIH-funded clinical trial to address healthcare disparities in hypertension management, research and education faculty at an academic medical center used a participatory action research approach to engage local community members to develop and refine a "knowledge, awareness, and skill-building" bias recognition and mitigation program. The program targeted medical residents and Doctor of Nursing Practice students. The content of the two-session training included: didactics about healthcare disparities, racism and implicit bias; implicit association test (IAT) administration to raise awareness of personal implicit bias; skill building for bias-mitigating communication; and case scenarios for skill practice in simulation-based encounters with standardized patients (SPs) from the local community. The initial trial year enrolled n = 65 interprofessional participants. Community partners and SPs who engaged throughout the design and implementation process reported overall positive experiences, but SPs expressed need for greater faculty support during in-person debriefings following simulation encounters to balance power dynamics. Initial year trainee participants reported discomfort with intensive sequencing of in-person didactics, IATs, and SP simulations in each of the two training sessions. In response, authors refined the training program to separate didactic sessions from IAT administration and SP simulations, and to increase safe space, and trainee and SP empowerment. The final program includes more interactive discussions focused on identity, race and ethnicity, and strategies to address local health system challenges related to structural racism. It is possible to develop and implement a bias awareness and mitigation skills training program that uses simulation-based learning with SPs, and to engage with local community members to tailor the content to address the experience of local patient populations. Further research is needed to measure the success and impact of replicating this approach elsewhere.

Perspectives of caregivers of older adults with acute myeloid leukemia during initial hypomethylating agents and venetoclax chemotherapy.

Older adults with AML commonly receive a hypomethylating agent (HMA) as first-line therapy. The addition of venetoclax (VEN) to HMAs has been shown to improve remission rates and overall survival. The use of combination therapy (HMA + VEN) requires frequent follow-up, results in longer infusion times, and likely increases caregiver responsibility at home. We describe experiences of informal caregivers (family/friends) providing care to older adults with AML receiving HMA + VEN. Fourteen caregivers of older adults with AML receiving HMA + VEN (September 2020 to September 2021) were recruited as part of a control group of an ongoing NIH-funded clinical trial. Semi-structured interviews were conducted to gain initial insight into caregiver experiences at the start of HMA + VEN treatment. Two researchers analyzed the data using thematic content analysis. Data saturation occurred when no new themes were found in subsequent interviews, but all interviews were coded and synthesized. Of the 14 caregivers interviewed, the majority were spouses (n = 10), female (n = 13), and aged 45 to 83 (median age 65). We identified five themes: (1) the impact of an AML diagnosis in older adulthood, (2) care recipient condition changes, (3) perspectives of caregiving roles and tasks, (4) factors influencing caregiving experiences, and (5) support system roles. Caregivers for older adults with AML report a range of experiences navigating health systems, caregiving responsibilities, and resource needs. The risk for caregiver burden and unmet needs should be addressed to improve caregivers' abilities to provide care.

Abstract 10200: Costs and Resource Utilization of People With Stable Heart Failure and Insomnia: Evidence From a Randomized Trial

Introduction: Nearly half of patients with chronic heart failure (HF) report insomnia symptoms. Cognitive behavioral therapy for insomnia (CBT-I) is efficacious for treating insomnia in the presence of comorbid conditions. This study estimated healthcare costs and resource utilization for people with stable chronic HF and insomnia using data from an NIH-funded clinical trial comparing CBT-I with an HF self-management Methods: Using data from the HeartSleep Study, we examined resource utilization one year following randomization. Resource utilization was measured as self-reported physician office visits, emergency department visits, and inpatient admissions, collected at each follow-up. Costs were estimated by applying price weights to visits, and adding self-reported out of pocket expenses and indirect costs. Univariate comparisons were made of resource utilization and costs between CBT-I and attention control groups. A generalized linear model (GLM) was used to model costs, controlling for covariates. Results: There were no significant differences in demographic characteristics between patients who received CBT-I (N=79) and those who received HF self-management (attention control) (N=71). During the first year following randomization, participants receiving CBT-I had 4.2 inpatient hospitalizations compared to 4.6 for the attention control group (p = 0.40). Participants receiving CBT-I also had 13.1 outpatient visits on average, while control participants had 15.4 outpatient visits. Relatively few emergency department visits were required by either CBT-I or attention-control participants. Overall, total costs were slightly higher for participants who received CBT-I ($7,813 vs. $7,538, p = 0.96). In the multivariable analysis participants who received CBT-I had $630 in higher costs, but this was not statistically different from the attention control group. Conclusions: Among patients with both HF and insomnia, CBT-I and HF self-management had similar resource utilization and total costs. Additional research is needed to estimate the value of CBT-I relative to other treatments for insomnia in patients with HF.

Eligibility criteria in NIH-funded clinical trials: Can adults with intellectual disability get in?

BackgroundAlthough scientific breakthroughs can promote health equity, there is concern that adults with intellectual disability, a health disparities population, may be excluded from clinical trials. ObjectiveTo determine the extent to which adults with intellectual disability are subject to exclusion from National Institutes of Health (NIH)-funded clinical trials. MethodsWe studied recent NIH-funded Phase 2/3, 3, and 4 clinical trials of United States-based working-age adults (>18 < 55 years of age) listed in ClinicalTrials.gov. We coded eligibility criteria for inclusion, direct exclusion, and indirect exclusion of adults with intellectual disability. ResultsWe rarely identified studies that directly include adults with intellectual disability. Most studies (74.6%) had eligibility criteria that directly and/or indirectly exclude adults with intellectual disability. Approximately one-third of studies had direct exclusion criteria based on cognitive impairment or diagnosis of intellectual disability. Nearly 65% of studies indirectly excluded adults with intellectual disability based on factors likely associated with intellectual disability (e.g., functional capacity, inability to read/write, and/or research staff discretion). ConclusionsWe found less exclusion based on diagnosis of intellectual disability than anticipated. Nonetheless, about three-fourths of studies had eligibility criteria which would likely lead to the direct and/or indirect exclusion of adults with intellectual disability. Our findings suggest substantial cause for concern that adults with intellectual disability experience widespread exclusion from NIH-funded clinical trials—exclusion that may lack appropriate justification and assessment. Consequently, this group is denied equal access to the potential benefits of scientific discovery. We provide recommendations for approaches to include adults with intellectual disability.

The Persistence of Sex Bias in High-Impact Clinical Research

IntroductionSex bias is present in clinical research resulting in disparities in the treatment of women. Our objective was to identify the prevalence of sex inclusiveness of participants in human clinical trials after the passage of National Institutes of Health (NIH) and United States Congress policies in 2015 and 2016 to increase female enrollment in clinical research. MethodsWe performed an observational analysis of data from registered clinical trials published in three high-impact biomedical journals from January 1, 2015 to December 31, 2019. ResultsOne thousand four hundred and forty two manuscripts with 4,765,783 human subjects were included for analysis. Significantly more males (56%) than females (44%) were included in all three journals (P < 0.0001). Sex matching ≥ 80% was found in 24.6% of publications. Industry funded 43.7% of all studies enrolling significantly more males than females (60.8% versus 39.2%, P < 0.0001). NIH funded 10.2% of studies enrolling significantly more females than males (52.7% versus 47.3%, P < 0.0001). North America and Europe contributed 82.6% of the studies with each enrolling significantly more males than females (P < 0.0001). The United States was the country contributing the most studies (36.1%), enrolling significantly more males than females (55.5% versus 45.5%, P < 0.0001). Cardiovascular disease was the subject area of the most manuscripts among medical specialties (19%), enrolling significantly more males than females (64.9% versus 35.1%, P < 0.0001). Studies analyzed by clinical trial phase, type, trial, and allocation enrolled significantly more males than females (P < 0.0001). ConclusionsSex bias remains prevalent in human clinical research trials. Improvements have been made in NIH-funded clinical trials; however, this constitutes a small percentage of overall studies.

Current status of inclusion of black subjects in neuropsychological studies: A scoping review and call to action

Objective: In recognition that insufficient diversity in research impedes the generalizability of findings and negatively impacts clinical outcomes, the 1993 National Institutes of Health (NIH) Revitalization Act required NIH-funded clinical trials to include and assess outcomes for women and minority participants. Since that time, the American Psychological Association (APA) and the American Academy of Clinical Neuropsychology (AACN) have also acknowledged the reporting of this information as an essential element of research, and they have established similar aspirational goals. Nevertheless, Black communities remain disproportionately underrepresented in neuropsychology research. The objective of this study was to investigate current levels of inclusion and reporting of Black research participation in neuropsychological studies. Methods: Publications from high impact neuropsychology journals between 2019–2020 were selected via established methodologies. Studies were analyzed to determine the rates of demographic inclusion and reporting of minority, particularly Black, participants. Results: A total of 1,764 articles were reviewed across seven neuropsychology journals. Of the 653 studies not excluded for other reasons, 43% neglected to include sufficient information about participants’ race/ethnicity. Of the subset of eligible studies that did include racial/ethnic demographic information (n = 349), only 61% included any Black participants at all. Only 34.1% of them included enough Black participants equal to or greater than the proportion of Black individuals within the United States. Conclusions: Setting a standard of routinely reporting and analytically reflecting on demographic information is necessary to make valid inferences regarding disease sequelae, treatment, and public health strategies. The authors offer specific recommendations to improve the inclusion and reporting of Black research participation, ensure compliance with established policies, and improve the quality of neuropsychological research.

Abstract 11350: DNP-PhD Collaboration in NIH-funded Physical Activity Trials for Women at Risk for Cardiovascular Disease: A Team Science Approach

Doctorally prepared nurse scholars with the doctor of nursing practice (DNP) and the doctor of philosophy (PhD) degrees are equally well suited to engage in scholarship to advance cardiovascular nursing and health outcomes. Collaboration between DNP and PhD scholars is crucial to develop interventions to improve cardiovascular outcomes and encourage efficient translation of research findings into practice. The purpose of this paper is to (1) provide a targeted review of the current state of literature on examples of DNP-PhD collaboration, and (2) describe ongoing DNP-PhD collaborations across three NIH-funded trials (1 completed, 2 ongoing) testing physical activity interventions for women at risk for cardiovascular disease. First, a targeted review was conducted to identify examples of DNP-PhD collaboration, and identified 12 published articles. Articles described the DNP-PhD collaborations in research/scholarship ( n = 8) and education ( n = 5). Of the research articles, there was evidence of collaboration in evidence-based practice projects for various health outcomes. However, none of the articles described DNP-PhD collaboration in NIH-funded clinical trials, including behavioral interventions for cardiovascular health. Three physical activity interventions for women at risk for cardiovascular disease were or are being tested in three trials (NCT01700894, NCT03558828, NCT04556305). Examples of DNP-PhD collaboration are categorized according to the four Team Science Phases. Research teams are led by PhD nurse scholars who oversee design and implementation (Development, Conceptualization, Implementation, Translation). DNP scholars provide clinical feedback in advisory panels and focus groups (Development, Conceptualization), provide training to intervention teams, lead personal call and group interventions (Implementation), facilitate patient referrals for participation (Implementation), oversee intervention safety (Implementation, Translation), and contribute to dissemination (Translation). DNP-PhD collaboration is important for all phases of NIH behavioral trials to optimize outcomes. There is a need for additional publications to detail applicable DNP-PhD collaborations in NIH-funded nursing research.

Rationale and design of a mechanistic clinical trial of JAK inhibition to prevent ventilator-induced diaphragm dysfunction

IntroductionVentilator-induced diaphragm dysfunction (VIDD) is an important phenomenon that has been repeatedly demonstrated in experimental and clinical models of mechanical ventilation. Even a few hours of MV initiates signaling cascades that result in, first, reduced specific force, and later, atrophy of diaphragm muscle fibers. This severe, progressive weakness of the critical ventilatory muscle results in increased duration of MV and thus increased MV-associated complications/deaths. A drug that could prevent VIDD would likely have a major positive impact on intensive care unit outcomes. We identified the JAK/STAT pathway as important in VIDD and then demonstrated that JAK inhibition prevents VIDD in rats. We subsequently developed a clinical model of VIDD demonstrating reduced contractile force of isolated diaphragm fibers harvested after ∼7 vs ∼1 h of MV during a thoracic surgical procedure. Materials and methodsThe NIH-funded clinical trial that has been initiated is a prospective, placebo controlled trial: subjects undergoing esophagectomy are randomized to receive 6 preoperative doses of the FDA-approved JAK inhibitor Tofacitinib (commonly used for rheumatoid arthritis) vs. placebo. The primary outcome variable will be the difference in the reduction that occurs in force generation of diaphragm single muscle fibers (normalized to their cross-sectional area), in the Tofacitinib vs. placebo subjects, over 6 h of MV. DiscussionThis trial represents a first-in-human, mechanistic clinical trial of a drug to prevent VIDD. It will provide proof-of-concept in human subjects whether JAK inhibition prevents clinical VIDD, and if successful, will support an ICU-based clinical trial that would determine whether JAK inhibition impacts clinical outcome variables such as duration of MV and mortality.

Update on RFA Increasing Use of Cardiac and Pulmonary Rehabilitation in Traditional and Community Settings NIH-Funded Trials: ADDRESSING CLINICAL TRIAL CHALLENGES PRESENTED BY THE COVID-19 PANDEMIC.

In Brief We previously described the design of six NIH-funded clinical trials designed to increase uptake and reduce disparities in the use of cardiac rehabilitation (CR) and pulmonary rehabilitation (PR) based on age, gender, race/ethnicity, and socioeconomic status. The onset of the COVID-19 global pandemic necessitated signifi cant revisions to the trials to ensure the safety of participants and research staff. This article described necessary modifi cations for assessments, interventions, and data collection to support a no-contact approach centered on the use of virtual/remote techniques that maintain both safety and the original intent and integrity of the trials. The general shift from site-based to home-based interventions and hybrid models of CR and PR will be increasingly important in a post-COVID world.

PD46-03 EXAMINING MINORITY ENROLLMENT IN CLINICAL TRIALS IN UROLOGIC ONCOLOGY

You have accessJournal of UrologyHealth Services Research: Practice Patterns, Quality of Life and Shared Decision Making IV (PD46)1 Sep 2021PD46-03 EXAMINING MINORITY ENROLLMENT IN CLINICAL TRIALS IN UROLOGIC ONCOLOGY Jeunice Owens-Walton, Cheyenne Williams, Alexis Rompre-Brodeur, Peter Pinto, and Mark W. Ball Jeunice Owens-WaltonJeunice Owens-Walton More articles by this author , Cheyenne WilliamsCheyenne Williams More articles by this author , Alexis Rompre-BrodeurAlexis Rompre-Brodeur More articles by this author , Peter PintoPeter Pinto More articles by this author , and Mark W. BallMark W. Ball More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002060.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Adequate representation in clinical trials is an important step towards addressing healthcare inequities. To explore the state of clinical trial representation within urologic cancers, we conducted a retrospective analysis comparing racial demographics in NIH-funded clinical trials with national cancer prevalence. METHODS: The ClinicalTrials.gov results database was queried for completed and resulted phase II and III, interventional clinical trials in the US funded by the NIH in prostate, kidney and bladder cancer. The Surveillance, Epidemiology, and End Results (SEER) database was queried for the prevalence of prostate, kidney and bladder cancer cases between 2000 and 2017. Representation Quotients (RQ) were calculated to describe the relative proportion of each demographic enrolled in a clinical trial over the proportion of those groups among national cancer cases. RESULTS: Seventy-five clinical trials met inclusion criteria with 59 of these reporting race and ethnicity. RQs were calculated for each race and ethnicity across each cancer type. Aggregates from 2000 to 2017 showed that White patients were overrepresented in trials for all cancer types (bladder cancer: RQ = 1.13 [1.11-1.15], kidney cancer: 1.28 [1.25-1.32], prostate cancer: 1.18 [1.16-1.20]). Black patients were adequately represented in prostate trials (0.95 [0.85-1.04] but underrepresented in kidney and bladder (0.75 [0.55-0.95] and 0.45 [0.26-0.64]). Asian patients were underrepresented in kidney and prostate trials (0.37 [0.22-0.51] and 0.67 [0.91 – 0.43]). Hispanic patients were underrepresented in kidney and prostate trials (0.52 [0.42 – 0.61] and 0.81[0.65-0.96], respectively). When stratified by 4-year increments and the RQs remained stable for all races, across all years in the study period. CONCLUSIONS: NIH funded clinical trials targeting prostate, kidney and bladder cancers continue to underrepresent minority patients. Based on the incidence of these cancers within minority populations there need to be improved and targeted efforts focused on creating racially and ethnically inclusive cancer research. Source of Funding: NIH Intramural Research Funding, NIH Medical Research Scholars Program, Foundation for the NIH © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e749-e749 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jeunice Owens-Walton More articles by this author Cheyenne Williams More articles by this author Alexis Rompre-Brodeur More articles by this author Peter Pinto More articles by this author Mark W. Ball More articles by this author Expand All Advertisement Loading ...

ECT-AD: Benefits and challenges of conducting a multisite NIH-funded clinical trial in a vulnerable population

Over 90% of individuals with Alzheimer's disease (AD) experience agitation which increase morbidity and mortality and contribute to caregiver burden. There are no FDA-approved treatments for severe agitation in people with advanced dementia. Psychotropic medications used off-label have limited efficacy and risk for adverse effects. Behavioral interventions are not effective in the most severely agitated patients. New management strategies for severe agitation in AD refractory to psychopharmacologic and behavioral interventions are timely and warranted. Preliminary studies provide evidence for the safety and efficacy of acute electroconvulsive therapy (ECT) in reducing agitation in this population. In this session we will describe lessons learned so far in the process of creating a multisite research consortium, designing a single blind, randomized clinical trial of ECT to determine efficacy and safety for severe agitation in advanced AD, applying for NIH grant, navigating regulations at the local, state, and federal level, and overcoming challenges with study implementation.

Coordinate-Based Network Mapping of Brain Structure in Major Depressive Disorder in Younger and Older Adults: A Systematic Review and Meta-Analysis

Background: Neuroimaging findings in younger and older adults with major depressive disorder (MDD) are highly heterogeneous. It is unclear whether this heterogeneity is due to methodological limitations, lack of distinction between MDD and late-life depression (LLD), or clinical moderators. Methods: We identified all voxel-based and surface-based morphometry studies comparing younger adults with MDD or older adults with LLD to non-psychiatric control participants (updated search: Oct 27, 2020). We used both an Activation Likelihood Estimation (ALE) analysis and a novel coordinate-based network mapping to identify brain circuits affected in MDD and LLD. We then used meta-regressions to examine the impact of age of onset in older patients with LLD and treatment with antidepressants in younger patients with MDD. Results: We analysed 145 comparisons from 143 articles including 14,318 participants (MDD; 6,362; LDD: 535; controls: 7,421). Our ALE results confirmed previous findings implicating the bilateral parahippocampus (z RIGHT =5.2, z LEFT =4.3, p FWE <0.001) and anterior cingulate (z RIGHT =3.6, z LEFT =4.5 p FWE <0.005) in MDD and anterior cingulate (z RIGHT =3.7, z LEFT =3.6 p FWE <0.005) in LLD. In contrast, coordinate-based network mapping showed differences in the frontoparietal, dorsal attention, and visual networks both in MDD and LLD. Meta-regressions showed that late onset was associated with widespread structural abnormalities in LLD and treatment with antidepressants was associated with abnormalities in the anterior cingulate (BA32, t 1,116 =3.8, p FDR =0.03) and dorsolateral prefrontal cortex (BA9, t 1,116 =3.0, p FDR =0.04) in MDD. Conclusions: While ALE identified specific brain regions affected in MDD, coordinate-based network mapping was more sensitive to disruptions in both MDD and LLD. Meta-regression identified additional differences related to age of onset and treatment with antidepressants. These findings help clarify the shared circuitry of depression across the adult lifespan and highlight some unique circuitry relevant to late-onset depression, which may explain some of the risk for cognitive decline and dementia. Funding Statement: Andrea Cipriani is supported by the National Institute for Health Research (NIHR) Oxford Cognitive Health Clinical Research Facility, by an NIHR Research Professorship (grant RP- 2017-08-ST2-006), by the NIHR Oxford and Thames Valley Applied Research Collaboration and by the NIHR Oxford Health Biomedical Research Centre (grant BRC-1215-20005). Declaration of Interests: PZ was funded by the Labatt Family Postdoctoral Fellowship in Depression Biology. JAEA was funded by Canadian Institute of Health Research CIHR fellowship Grant No. CIHR-IRSC: 0093005620. B.H. Mulsant receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto; he currently receives research support from Brain Canada, the Canadian Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute (PCORI), the US National Institute of Health (NIH), Capital Solution Design LLC (software used in a study founded by CAMH Foundation), and HAPPYneuron (software used in a study funded by Brain Canada). He directly owns stocks of General Electric (less than $5,000). Within the past five years, he has also received research support from Eli Lilly (medications and matching placebo pills for a NIH-funded clinical trial) and Pfizer (medications for a NIH-funded clinical trial) and he has been an unpaid consultant to Myriad Neuroscience. Andrea Cipriani has received research and consultancy fees from INCiPiT (Italian Network for Paediatric Trials), CARIPLO Foundation and Angelini Pharma. ANV currently receives funding from CIHR, the NIH, the National Sciences and Engineering Research Council (NSERC), the CAMH Foundation, and the University of Toronto.

Editorial introductions

Editorial introductions

Effects of Antipsychotic Medications on Brain Structure: Data from a Randomized, Double-Blind Placebo-Controlled Study

Effects of Antipsychotic Medications on Brain Structure: Data from a Randomized, Double-Blind Placebo-Controlled Study

Sex Bias in Interventional Clinical Trials.

Prior studies have shown that sex bias exists with subject enrollment in clinical trials, with more men being enrolled than women. The objective of this study was to identify if sex bias continues to exist in present day clinical trials entered into ClinicalTrials.gov . We hypothesize that males and females are not equally represented in recent clinical trials. Data were abstracted from all interventional Phase I, II, and III clinical trials with adult subjects entered into ClinicalTrials.gov from January 1, 2011 to December 31, 2013 and completed by November 30, 2015. Number and sex of subjects, funding source, allocation, end point classification, interventional model, and purpose were recorded. Studies pertaining to diseases that were sex specific were excluded. Of 1,668 studies included in the initial search, 167 were excluded due to sex-specific study topic. Of the remaining 1,501 studies, 177,656 (51.1%) male and 170,331 (49.0%) female subjects were included. There was a significant difference in the sex of the subjects included in Phase I (64.1% male/35.9% female), Phase II (48.4% male/51.6% female), and Phase III (51.0% male/49.1% female) clinical trials (p < 0.05). Similarly, there was a significant difference in the sex of the subjects included in industry (50.7% male/49.3% female), National Institutes of Health (NIH) (56.6% male/43.4% female), "Other US Federal" (62.5% male/37.5% female), and "Other" funded (53.4% male/46.6% female) clinical trials (p < 0.0001), as well as between randomized (50.5% male/49.6% female) and nonrandomized (54.8% male/45.2% female) clinical trials (p < 0.0001). Upon evaluating if the sex of the subjects included in the individual clinical trials was equally matched, we found that only 4.1% of clinical trials had 100% sex matching, 22.2% had 80% sex matching, and 56.5% had 50% sex matching. Using a liberal 50% sex-matching criteria, Phase III and II clinical trials matched the sex of the subjects more frequently compared to Phase I trials (60.8%, 57.8%, and 45.5%, respectively, p = 0.003). These data reveal that sex bias is present in current day clinical trials. Despite legislation requiring NIH-funded clinical trials to include women, NIH-funded trials were not better than industry-funded trials at matching the inclusion of both sexes.

(Can't Get No) Patient Satisfaction: The Predictive Power of Demographic, GI, and Psychological Factors in IBS Patients.

The goal of this study is to assess: (1) the relative contribution of patient factors to satisfaction ratings in irritable bowel syndrome (IBS) patients and (2) the relationship between patient satisfaction (PS) and the number of diagnostic tests patients underwent prior to receiving IBS diagnosis. Although PS is regarded as an important indicator of quality of care, little is known about its determinants. A total of 448 Rome III-diagnosed patients (M age=41 y; 79% F), whose GI symptoms were at least moderate in severity completed patient-reported outcome measures as part of pretreatment evaluation of an NIH-funded clinical trial. PS was measured with the 11-point Hospital Consumer Assessment of Healthcare Providers and Systems global rating scale modified to assess for IBS treatments. A series of multiple regression analyses were conducted for demographic, IBS-specific, general physical health, and psychological predictors before running a final model of significant predictors from each domain. The final regression model was significant, F6,419=6.34, P<0.001, R=0.08, with race, insurance, number of diagnostic tests, and lower neuroticism predicting PS. Medical tests were rendered nonsignificant when history of seeking care from a gastroenterologist was introduced into the equation. Contrary to hypotheses, neither the IBS symptom severity nor quality of life impairment predicted PS. Patient factors such as a neurotic personality style and sociodemographic profile had a significant but modest impact on PS. Pattern of regression analyses suggests that patients may turn to their gastroenterologist for testing for reassurance, which may in the long-term fuel demand for more testing.

2015 Behavioral clinical trials: Considerations for design and conduct using the new NIH study protocol template

OBJECTIVES/SPECIFIC AIMS: (1) To discuss key differences of behavioral clinical trials from trials involving drugs, devices, and biologics and (2) to discuss NIH efforts to provide a study protocol template for use by investigators conducting behavioral clinical trials. METHODS/STUDY POPULATION: A working group was convened by NIH to refine the commonly used protocol template required for investigators conducting Phase 2 or 3 NIH-funded clinical trials. The committee met by phone regularly for 4 months to review, discuss, and refine each section of the template as needed to include aspects relevant to behavioral trials. RESULTS/ANTICIPATED RESULTS: The behavioral trial protocol template draft has been created and is being further modified by feedback from the research community. DISCUSSION/SIGNIFICANCE OF IMPACT: Use of the NIH behavioral trial protocol template is expected to enhance the quality of any behavioral study, because the template and supporting materials were developed with the unique aspects of behavioral research in mind.