Designing and implementing methodology for double-blind, placebo-controlled clinical trials using blood products within the Department of Veterans Affairs.

BACKGROUND: Success in conducting clinical trials during the coronavirus disease of 2019 pandemic requires the ability to innovate and adapt. There are well-established procedures for the blinding of investigational agents, especially medications, in placebo-controlled randomized clinical trials within the Veterans Health Administration. However, these procedures, managed by research pharmacists, may not apply to investigational agents that are not exclusively managed by pharmacy, such as blood products, including coronavirus disease of 2019 convalescent plasma (plasma). In the absence of established blinding procedures, such studies require special design considerations to minimize uncertainty or bias. METHODS: We describe the processes and procedures developed for blinding of plasma in "Veterans Affairs CoronavirUs Research and Efficacy Studies-1" as a prototypical study using this class of investigational therapeutic agents. Veterans Affairs CoronavirUs Research and Efficacy Studies-1 is an ongoing multicenter randomized clinical trial testing the efficacy of plasma added to conventional therapy for severe acute respiratory syndrome coronavirus-2 infection. RESULTS: We report the design of procedures to supply investigational blood products or 0.9% normal saline (saline) control while ensuring the integrity of the blind. Key aspects include workflow considerations, physical blinding strategies, and methods for engaging stakeholders. These procedures leverage the well-established Veterans Affairs research pharmacist's research infrastructure, and Blood Bank Services, which is responsible for blood-based investigational products. CONCLUSION: By describing the methods used to deliver blood products in a blinded manner in Veterans Affairs CoronavirUs Research and Efficacy Studies-1, we strive both to educate and to increase awareness to improve the implementation of these biological therapeutics for future, high-quality research studies.

Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial.

IMPORTANCE: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant. OBJECTIVE: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD. DESIGN, SETTING, AND PARTICIPANTS: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks. INTERVENTIONS: Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase). MAIN OUTCOMES AND MEASURES: The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects. RESULTS: Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain. CONCLUSIONS AND RELEVANCE: Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01421342.

Prevalence of Post-Traumatic Stress Disorder in Aging Vietnam-Era Veterans: Veterans Administration Cooperative Study 569: Course and Consequences of Post-Traumatic Stress Disorder in Vietnam-Era Veteran Twins.

OBJECTIVE: The prevalence of post-traumatic stress disorder (PTSD) among aging Vietnam-era veterans is not well characterized. METHODS: In a cross-sectional study, 5,598 male Vietnam-era veterans and members of the Vietnam Era Twin Registry were assessed for PTSD using the Composite International Diagnostic Interview. Current symptoms were measured with the PTSD Checklist (PCL). PTSD was estimated according to age (<60 or ≥ 60) and Vietnam theater service. RESULTS: The lifetime prevalence of PTSD in theater veterans aged at least 60 years was 16.9% (95% CI: 13.9%-20.5%) and higher than the 5.5% (95% CI: 4.3%-7.0%) among nontheater veterans. Among veterans younger than 60 years, the comparable prevalence was 22.0% for theater (95% CI: 16.7%-28.4%) and 15.7% for nontheater (95% CI: 13.4%-18.2%) veterans. Similar results were found for theater service and current PTSD prevalence (past 12 months). PCL scores were significantly higher in theater compared with nontheater veterans in both younger and older cohorts. In both the younger and older cohorts significant differences in lifetime and current PTSD prevalence and PCL scores persisted in theater service discordant twin pairs. CONCLUSION: Vietnam service is related to elevated PTSD prevalence and current symptom burden in aging veterans. More than 30 years after the end of the Vietnam conflict, many veterans continue to suffer from PTSD, which highlights the need for continuing outreach throughout the life course.

Long-Term Trajectories of PTSD in Vietnam-Era Veterans: The Course and Consequences of PTSD in Twins.

We estimated the temporal course of posttraumatic stress disorder (PTSD) in Vietnam-era veterans using a national sample of male twins with a 20-year follow-up. The complete sample included those twins with a PTSD diagnostic assessment in 1992 and who completed a DSM-IV PTSD diagnostic assessment and a self-report PTSD checklist in 2012 (n = 4,138). Using PTSD diagnostic data, we classified veterans into 5 mutually exclusive groups, including those who never had PTSD, and 4 PTSD trajectory groups: (a) early recovery, (b) late recovery, (c) late onset, and (d) chronic. The majority of veterans remained unaffected by PTSD throughout their lives (79.05% of those with theater service, 90.85% of those with nontheater service); however, an important minority (10.50% of theater veterans, 4.45% of nontheater veterans) in 2012 had current PTSD that was either late onset (6.55% theater, 3.29% nontheater) or chronic (3.95% theater, 1.16% nontheater). The distribution of trajectories was significantly different by theater service (p < .001). PTSD remains a prominent issue for many Vietnam-era veterans, especially for those who served in Vietnam.

The association of PTSD with physical and mental health functioning and disability (VA Cooperative Study #569: the course and consequences of posttraumatic stress disorder in Vietnam-era veteran twins).

PURPOSE: To assess the relationship of posttraumatic stress disorder (PTSD) with health functioning and disability in Vietnam-era Veterans. METHODS: A cross-sectional study of functioning and disability in male Vietnam-era Veteran twins. PTSD was measured by the Composite International Diagnostic Interview; health functioning and disability were assessed using the Veterans RAND 36-Item Health Survey (VR-36) and the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). All data collection took place between 2010 and 2012. RESULTS: Average age of the 5,574 participating Veterans (2,102 Vietnam theater and 3,472 non-theater) was 61.0 years. Veterans with PTSD had poorer health functioning across all domains of VR-36 and increased disability for all subscales of WHODAS 2.0 (all p < .001) compared with Veterans without PTSD. Veterans with PTSD were in poorer overall health on the VR-36 physical composite summary (PCS) (effect size = 0.31 in theater and 0.47 in non-theater Veterans; p < .001 for both) and mental composite summary (MCS) (effect size = 0.99 in theater and 0.78 in non-theater Veterans; p < .001 for both) and had increased disability on the WHODAS 2.0 summary score (effect size = 1.02 in theater and 0.96 in non-theater Veterans; p < .001 for both). Combat exposure, independent of PTSD status, was associated with lower PCS and MCS scores and increased disability (all p < .05, for trend). Within-pair analyses in twins discordant for PTSD produced consistent findings. CONCLUSIONS: Vietnam-era Veterans with PTSD have diminished functioning and increased disability. The poor functional status of aging combat-exposed Veterans is of particular concern.

Analysis of a national response to a White House directive for ending veteran suicide.

OBJECTIVE: Analyze responses to a national request for information (RFI) to uncover gaps in policy, practice, and understanding of veteran suicide to inform federal research strategy. DATA SOURCE: An RFI with 21 open-ended questions generated from Presidential Executive Order #1386, administered nationally from July 3 to August 5, 2019. STUDY DESIGN: Semi-structured, open-ended responses analyzed using a collaborative qualitative and text-mining data process. DATA EXTRACTION METHODS: We aligned traditional qualitative methods with natural language processing (NLP) text-mining techniques to analyze 9040 open-ended question responses from 722 respondents to provide results within 3 months. Narrative inquiry and the medical explanatory model guided the data extraction and analytic process. RESULTS: Five major themes were identified: risk factors, risk assessment, prevention and intervention, barriers to care, and data/research. Individuals and organizations mentioned different concepts within the same themes. In responses about risk factors, individuals frequently mentioned generic terms like "illness" while organizations mentioned specific terms like "traumatic brain injury." Organizations and individuals described unique barriers to care and emphasized ways to integrate data and research to improve points of care. Organizations often identified lack of funding as barriers while individuals often identified key moments for prevention such as military transitions and ensuring care providers have military cultural understanding. CONCLUSIONS: This study provides an example of a rapid, adaptive analysis of a large body of qualitative, public response data about veteran suicide to support a federal strategy for an important public health topic. Combining qualitative and text-mining methods allowed a representation of voices and perspectives including the lived experiences of individuals who described stories of military transition, treatments that worked or did not, and the perspective of organizations treating veterans for suicide. The results supported the development of a national strategy to reduce suicide risks for veterans as well as civilians.

Plaque Regression and Endothelial Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen (PREMIER).

BACKGROUND: Low-density lipoproteins (LDLs) are removed by extracorporeal filtration during LDL apheresis. It is mainly used in familial hyperlipidemia. The PREMIER trial (Plaque Regression and Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen) evaluated LDL apheresis in nonfamilial hyperlipidemia acute coronary syndrome patients treated with percutaneous coronary intervention. METHODS: We randomized 160 acute coronary syndrome patients at 4 Veterans Affairs centers within 72 hours of percutaneous coronary intervention to intensive lipid-lowering therapy (ILLT) comprising single LDL apheresis and statins versus standard medical therapy (SMT) with no LDL apheresis and statin therapy alone. Trial objectives constituted primary safety and primary efficacy end points and endothelial progenitor cell colony-forming unit mobilization in peripheral blood. RESULTS: Mean LDL reduction at discharge was 53% in ILLT and 17% in SMT groups (P<0.0001) from baseline levels of 116.3±34.3 and 110.7±32 mg/dL (P=0.2979), respectively. The incidence of the primary safety end point of major peri-percutaneous coronary intervention adverse events was similar in both groups (ILLT, 3; SMT, 0). The primary efficacy end point, percentage change in total plaque volume at 90 days by intravascular ultrasound, on average decreased by 4.81% in the ILLT group and increased by 2.31% in the SMT group (difference of means, -7.13 [95% CI, -14.59 to 0.34]; P=0.0611). The raw change in total plaque volume on average decreased more in the ILLT group than in the SMT group (-6.01 versus -0.95 mm3; difference of means, -5.06 [95% CI, -11.61 to 1.48]; P=0.1286). Similar results were obtained after adjusting for participating sites, age, preexisting coronary artery disease, diabetes mellitus, baseline LDL levels, and baseline plaque burden. There was robust endothelial progenitor cell colony-forming unit mobilization from baseline to 90 days in the ILLT group (P=0.0015) but not in SMT (P=0.0844). CONCLUSIONS: PREMIER is the first randomized clinical trial to demonstrate safety and a trend for early coronary plaque regression with LDL apheresis in nonfamilial hyperlipidemia acute coronary syndrome patients treated with percutaneous coronary intervention. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01004406 and NCT02347098.

Noncommercial US Funders' Policies on Trial Registration, Access to Summary Results, and Individual Patient Data Availability.

Importance: Incomplete information about existing research is an underlying cause of research waste. National and international initiatives and requirements have been launched to address this issue. Objectives: To characterize current clinical trial transparency policies among the largest noncommercial US funders and examine whether the policies are concordant with international funders. Design, Setting, and Participants: This retrospective review of public information used methods developed for documenting funder policies internationally; 2 researchers searched each funder's website and Google between May and November 2018 to locate trial transparency policies for 10 top US funders. Key informants at each funding organization were contacted by email and given 3 or more weeks to review and confirm or correct the findings. Nonresponders were contacted 2 or more additional times. Descriptive statistics were calculated to summarize the findings. The study was conducted using publicly available policy information with findings confirmed by funder representatives where possible. Participants included top 10 noncommercial US health research funders with the highest reported investment in health research (2013 dollars) who fund clinical trials. Data analysis was conducted from November 6, 2018, to November 23, 2018. Exposures: Availability of policies addressing each of the 3 key trial transparency domains as specified by the World Health Organization in 2017. Main Outcomes and Measures: Independent assessment by 2 investigators of availability (yes or no) of a policy addressing registration for trials, sharing of summary results, and individual participant data sharing activities; requirements (yes, no, or supportive statement) of these policies in terms of completeness, timeliness, public access, and provision of additional technical or financial support to meet data sharing requirements; description (yes or no) of internal monitoring for policy adherence. Results: All 10 funders acknowledged the outreach. One funder who indicated that less than 1% of their research funding goes to clinical trials was removed. Six (67%) of the remaining 9 top US funders have a publicly available written policy for all 3 major trial transparency domains. The most comprehensive trial transparency practice among US funders addresses summary results sharing as follows: 8 of 9 US funders (89%) have a policy, 5 of 9 US funders (56%) require reporting of summary results within 1 year, and 6 of 9 US funders (67%) monitor compliance with their summary results sharing policy. For clinical trial registration, 7 of 9 US funders (78%) have a policy and 5 of 9 US funders (56%) require registration and monitor trial registration to measure adherence to the policy. Conclusions and Relevance: In this study, overall the proportion of US funders with policies and practices to support trial transparency in this sample was similar or compared favorably with the larger international sample of noncommercial funders recently reported.

Physical Health Conditions Among a Population-Based Cohort of Vietnam-Era Women Veterans: Agreement Between Self-Report and Medical Records.

BACKGROUND: Little is known about medical morbidity among women Vietnam-era veterans, or the long-term physical health problems associated with their service. This study assessed agreement comparing data on physical health conditions from self-report and medical records from a population-based cohort of women Vietnam-era Veterans from the Health of Vietnam Era Women's Study (HealthViEWS). MATERIALS AND METHODS: Women Vietnam-era veterans (n = 4219) self-completed a survey and interview on common medical conditions. A subsample (n = 900) were contacted to provide permission to obtain medical records from as many as three of their providers. Medical record reviews were conducted using a standardized checklist. Agreement and kappa (agreement beyond chance) were calculated for physical health condition groups. RESULTS: Of the 900, 449 had medical records returned, and of those, 412 had complete surveys/interviews. The most commonly reported conditions based on self-report or medical record review included hypertension, hyperlipidemia, or arthritis. Kappa scores between self-reported conditions and medical record documentation were 0.75-0.91 for hypertension, diabetes, most cancers, and neurological conditions, but lower (k = 0.29-0.55) for cardiovascular diseases, musculoskeletal, and gastrointestinal conditions. Generally, agreement did not significantly vary by different sociodemographic groups. CONCLUSIONS: There was relatively high agreement for physical health conditions when self-report was compared with medical record review. As more women are increasingly represented in the military and more veterans in general seek care outside the Veterans Health Administration, accurate measurement of physical health conditions among population-based samples is crucial.

The VA augmentation and switching treatments for improving depression outcomes (VAST-D) study: Rationale and design considerations.

Because two-thirds of patients with Major Depressive Disorder do not achieve remission with their first antidepressant, we designed a trial of three "next-step" strategies: switching to another antidepressant (bupropion-SR) or augmenting the current antidepressant with either another antidepressant (bupropion-SR) or with an atypical antipsychotic (aripiprazole). The study will compare 12-week remission rates and, among those who have at least a partial response, relapse rates for up to 6 months of additional treatment. We review seven key efficacy/effectiveness design decisions in this mixed "efficacy-effectiveness" trial.

Posttraumatic stress disorder and incidence of type-2 diabetes: a prospective twin study.

Growing evidence has linked posttraumatic stress disorder (PTSD) to insulin resistance and type-2 diabetes, but most previous studies were cross-sectional. We examined the association between PTSD and incidence of diabetes in a prospective study of middle-aged male twins from the Vietnam Era Twin Registry. Lifetime PTSD was diagnosed at baseline with the Diagnostic Interview Schedule (DIS) according to DSM-III-R criteria. Subthreshold PTSD was defined by meeting some, but not all, criteria for PTSD. A total of 4340 respondents without self-reported diabetes at baseline were included. Of these, 658 reported a new diagnosis of treated diabetes over a median of 19.4 years of follow-up. At baseline, twins with PTSD showed more behavioral and metabolic risk factors such as overweight and hypertension. The age-adjusted cumulative incidence of diabetes was significantly higher in twins with PTSD (18.9%) than those without PTSD (14.4%), [odds ratio (OR) = 1.4, 95% confidence interval (CI) 1.03-1.8], and intermediate in those with subthreshold PTSD (16.4%) (OR = 1.2, 95% CI 0.9-1.5, p for trend = 0.03). Adjustment for military, lifestyle and metabolic factors diminished the association. No significant association was found comparing twin pairs discordant for PTSD. In conclusion, PTSD was prospectively associated with a 40% increased risk of new-onset type-2 diabetes which was partially explained by a cluster of metabolic and behavioral risk factors known to influence insulin resistance. Shared biological or behavioral precursors which occur within families may lead to both PTSD and insulin resistance/diabetes. Thus, PTSD could be a marker of neuroendocrine and metabolic dysregulation which may lead to type-2 diabetes.