Patient- reported reasons for non-participation in a COVID-19 therapeutics clinical trial: Findings from a multi-center investigation.

BACKGROUND: Early in the pandemic, there were no evidence-based treatments for SARS-CoV-2, creating an urgent need to identify effective therapeutics. However, public participation in medical research is low; trial enrollment in the US is typically 10-20%. Thus, the aim of this study was to identify common themes underpinning patient reasons to decline participation and evaluate the impact of specific contextual factors. METHODS: This sub-study was conducted in five VISN-1 Clinical Trials Network participating facilities from 4/10/2020-2/3/2021. The trial evaluated the addition of the IL-6-inhibitor, Sarilumab, to the current standard of care for inpatients with moderate-to-severe SARS-CoV-2. Consent procedures varied by site and included fully in-person and fully remote processes. Reasons for declining enrollment were collected among eligible patients who declined to participate but agreed to answer a short follow-up question. Qualitative data were analyzed using directed content analysis. Enrollment rates were assessed using simple, descriptive statistics. RESULTS: N = 417 COVID-19 positive inpatients were screened and 53/162 eligible patients enrolled. Enrollment varied across study sites and by study period. Prior to identification of effective treatment, the enrollment rate was 10/11 (91%) versus 43/144 (30%) during the later period of the study. N = 85/102 patients who did not enroll answered the follow-up question. The most commonly reported responses were: concerns about the study drug and participation in clinical research in general, comorbidity concerns, competing priorities, external factors, and external advice and influence from family members and clinicians. CONCLUSIONS: Identifying reasons behind declining to enroll may help investigators develop strategies to increase research participation.

Subcutaneous sarilumab for the treatment of hospitalized patients with moderate to severe COVID19 disease: A pragmatic, embedded randomized clinical trial.

IMPORTANCE AND OBJECTIVE: The aim of this pragmatic, embedded, adaptive trial was to measure the effectiveness of the subcutaneous anti-IL-6R antibody sarilumab, when added to an evolving standard of care (SOC), for clinical management of inpatients with moderate to severe COVID-19 disease. DESIGN: Two-arm, randomized, open-label controlled trial comparing SOC alone to SOC plus sarilumab. The trial used a randomized play-the-winner design and was fully embedded within the electronic health record (EHR) system. SETTING: 5 VA Medical Centers. PARTICIPANTS: Hospitalized patients with clinical criteria for moderate to severe COVID-19 but not requiring mechanical ventilation, and a diagnostic test positive for SARS-CoV-2. INTERVENTIONS: Sarilumab, 200 or 400 mg subcutaneous injection. SOC was not pre-specified and could vary over time, e.g., to include antiviral or other anti-inflammatory drugs. MAIN OUTCOMES AND MEASURES: The primary outcome was intubation or death within 14 days of randomization. All data were extracted remotely from the EHR. RESULTS: Among 162 eligible patients, 53 consented, and 50 were evaluated for the primary endpoint of intubation or death. This occurred in 5/20 and 1/30 of participants in the sarilumab and SOC arms respectively, with the majority occurring in the initial 9 participants (3/4 in the sarilumab and 1/5 in the SOC) before the sarilumab dose was increased to 400 mg and before remdesivir and dexamethasone were widely adopted. After interim review, the unblinded Data Monitoring Committee recommended that the study be stopped due to concern for safety: a high probability that rates of intubation or death were higher with addition of sarilumab to SOC (92.6%), and a very low probability (3.4%) that sarilumab would be found to be superior. CONCLUSIONS AND RELEVANCE: This randomized trial of patients hospitalized due to respiratory compromise from COVID-19 but not mechanical ventilation found no benefit from subcutaneous sarilumab when added to an evolving SOC. The numbers of patients and events were too low to allow definitive conclusions to be drawn, but this study contributes valuable information about the role of subcutaneous IL-6R inhibition in the treatment of hospitalized COVID-19 patients. Methods developed and piloted during this trial will be useful in conducting future studies more efficiently. TRIAL REGISTRATION: Clinicaltrials.gov-NCT04359901; https://clinicaltrials.gov/ct2/show/NCT04359901?cond=NCT04359901&draw=2&rank=1.

Lithium Treatment in the Prevention of Repeat Suicide-Related Outcomes in Veterans With Major Depression or Bipolar Disorder: A Randomized Clinical Trial.

Importance: Suicide and suicide attempts are persistent and increasing public health problems. Observational studies and meta-analyses of randomized clinical trials have suggested that lithium may prevent suicide in patients with bipolar disorder or depression. Objective: To assess whether lithium augmentation of usual care reduces the rate of repeated episodes of suicide-related events (repeated suicide attempts, interrupted attempts, hospitalizations to prevent suicide, and deaths from suicide) in participants with bipolar disorder or depression who have survived a recent event. Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial assessed lithium vs placebo augmentation of usual care in veterans with bipolar disorder or depression who had survived a recent suicide-related event. Veterans at 29 VA medical centers who had an episode of suicidal behavior or an inpatient admission to prevent suicide within 6 months were screened between July 1, 2015, and March 31, 2019. Interventions: Participants were randomized to receive extended-release lithium carbonate beginning at 600 mg/d or placebo. Main Outcomes and Measures: Time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide. Results: The trial was stopped for futility after 519 veterans (mean [SD] age, 42.8 [12.4] years; 437 [84.2%] male) were randomized: 255 to lithium and 264 to placebo. Mean lithium concentrations at 3 months were 0.54 mEq/L for patients with bipolar disorder and 0.46 mEq/L for patients with major depressive disorder. No overall difference in repeated suicide-related events between treatments was found (hazard ratio, 1.10; 95% CI, 0.77-1.55). No unanticipated safety concerns were observed. A total of 127 participants (24.5%) had suicide-related outcomes: 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and 3 in the placebo group. Conclusions and Relevance: In this randomized clinical trial, the addition of lithium to usual Veterans Affairs mental health care did not reduce the incidence of suicide-related events in veterans with major depression or bipolar disorders who experienced a recent suicide event. Therefore, simply adding lithium to existing medication regimens is unlikely to be effective for preventing a broad range of suicide-related events in patients who are actively being treated for mood disorders and substantial comorbidities. Trial Registration: ClinicalTrials.gov Identifier: NCT01928446.

Implementation of documented and written informed consent for clinical trials of communicable diseases: Lessons learned, barriers, solutions, future directions identified during the conduct of a COVID-19 clinical trial.

BACKGROUND AND OBJECTIVE: The communicable nature of many infectious diseases, including SARS-CoV-2, creates challenges for implementing and obtaining regulatory-compliant written informed consent. The goal of this project was to identify and evaluate processes that address these barriers while maintaining clinical and research staff safety. METHODS: We reviewed Federal Drug Administration (FDA), World Health Organization (WHO), and VA Office of Research and Development (ORD) guidance about informed consent during the COVID-19 pandemic, and identified and pilot-tested several mechanisms for obtaining regulatory-compliant consent during our COVID-19 therapeutics clinical trial. RESULTS: Several processes were identified. These included a standard face-to-face consent with a plan for maintaining a paper copy of the signed consent form, a phone or video chat consent process that included taking a picture of the signed consent form or a screen shot of the signed document during a video chat, integration of the consent forms into software embedded within the electronic health record, and secure software programs with electronic signature. These processes are FDA-compliant but time-intensive, often requiring four or more hours of coordination between the clinical team, research staff, patients, and legally authorized representatives. CONCLUSIONS: Future studies could evaluate how to improve efficiency, and whether some elements of the consenting process, such as the requirement for documented written signed consent, rather than a witnessed oral consent, is an acceptable standard for research participants with communicable diseases.

The association between height and prostate cancer grade in the Early Stage Prostate Cancer Cohort Study.

OBJECTIVE: We examined the relationship between height and prostate cancer grade. METHODS: The Early Stage Prostate Cancer Cohort Study is an observational cohort of 1,037 men diagnosed with early-stage prostate cancer, T(0-3)N(x)M(0). High-grade prostate cancer was defined as a biopsy Gleason score ≥ 7 (4 + 3). Logistic regression models were created to calculate odds ratios (OR) and 95% confidence intervals (CI) for the cross-sectional relationship between height and prostate cancer grade in the overall cohort and subpopulations. RESULTS: We identified 939 participants with a biopsy Gleason score. High-grade prostate cancer was diagnosed in 138 participants. Overall, participants in the highest quartile of height were more than twice as likely to have a Gleason score ≥ 7 (4 + 3) than participants in the lowest quartile of height, OR 2.14 (95% CI 1.11, 4.14), after multivariate adjustment. Participants in the highest quartile of height were more likely to be diagnosed with high-grade prostate cancer than participants in the lowest quartile of height among participants who were black, OR 8.00 (95% CI 1.99, 32.18), and participants who had diabetes mellitus, OR 5.09 (95% CI 1.30, 19.98). CONCLUSIONS: Height is associated with increased risk of high-grade prostate cancer overall and perhaps among certain subpopulations.

Practitioner-level determinants of inappropriate prostate-specific antigen screening.

BACKGROUND: None of the major clinical practice guidelines recommend that prostate-specific antigen (PSA) screening be routinely performed in asymptomatic men older than 75 years or younger than 40 years. We investigated the practitioner-level determinants of inappropriate PSA screening in 7 Veterans Health Administration (VHA) hospitals. METHODS: Data on PSA test use from 1997 to 2004 were obtained from VHA databases for 181 139 male patients and the 4823 health care providers who ordered their tests. Patients were excluded from the study population if they underwent PSA testing for nonscreening reasons, as indicated by prostate cancer-specific medications, diagnoses, and procedures. Inappropriate PSA test use was defined as PSA screening in patients older than 75 years or younger than 40 years. Univariate and multivariate Poisson regressions were performed. RESULTS: The mean +/- SD percentage of inappropriate tests by health care provider was 19.3% +/- 15.0%, with 18.4% +/- 14.9% in patients older than 75 years and 0.8% +/- 3.0% in patients younger than 40 years. Practitioners who were urology specialists, male, infrequent PSA test orderers, and affiliated with specific hospitals had significantly higher levels of inappropriate PSA screening. Compared with attending physicians, nurses and physician assistants had significantly lower levels of inappropriate screening. Under multivariate modeling, infrequent PSA test ordering and hospital affiliation retained statistical significance. The percentage of inappropriate PSA screening increased significantly with the age of male health care providers (P<.001). CONCLUSIONS: This study elucidates several important provider-level determinants of PSA screening misuse and substantiates that PSA screening is frequently performed counter to evidence-based guidelines. Further work is needed to determine the degree to which "prostatempathy" contributes to PSA misuse by older male providers.

Randomized controlled trial of prophylactic repair of hemodialysis arteriovenous graft stenosis.

BACKGROUND: Previous nonrandomized studies suggest that prophylactic repair of hemodialyisis arteriovenous (AV) graft stenosis reduces thrombosis rates and increases cumulative graft survival. The present study is a randomized trial comparing prophylactic repair of AV graft stenosis with repair at the time of thrombosis. METHODS: Sixty-four patients with elevated static venous pressure measured in an upper extremity AV graft were randomized to Intervention or Observation. Monthly static venous pressure/systolic blood pressure ratios (SVPR) were determined for all patients throughout the duration of study participation. Patients in the Intervention group underwent angiography and repair of identified stenoses if the monthly SVPR was elevated (>/=0.4). Patients in the Observation group underwent stenosis repair only in the event of access thrombosis or clinical evidence of access dysfunction. The primary end point was access abandonment. RESULTS: Access abandonment occurred in 14 patients in the Intervention group and 14 patients in the Observation group during the 3.5-year study period. Time to access abandonment did not differ significantly between the treatment groups (hazard ratio for randomization to Intervention 1.75, 95% CI 0.80-3.82, P= 0.16). The proportion of patients with a thrombotic event was greater in the Observation group (72%) than in the Intervention group (44%) (P= 0.04), but overall thrombosis rates were similar in the groups. CONCLUSION: Compared with a strategy of observation and repair of accesses only in the event of thrombosis, prospective static venous pressure monitoring with prophylactic stenosis repair did not prolong graft survival.

Value of static venous pressure for predicting arteriovenous graft thrombosis.

BACKGROUND: Static venous pressure elevation has been shown to have both high sensitivity and high specificity for hemodialysis arteriovenous (AV) graft venous anastomosis stenosis. However, it is not known how well static venous pressure elevation predicts subsequent AV graft thrombosis. METHODS: Monthly static venous pressure measurements were made during two consecutive dialysis sessions in all patients with a functioning upper extremity AV graft in two hemodialysis units during a 16-month period. Static venous pressure was normalized to systolic blood pressure and corrected for the height difference between the AV graft and the dialysis machine pressure transducer to yield the static venous pressure ratio (SVPR). RESULTS: Fifty-four patients (38%) had a thrombotic event during the study period and thus were labeled as clotters. Among the clotters, SVPR just prior to thrombosis was 0.51 +/- 0.16 (mean +/- SD), and mean time to thrombosis following an elevated SVPR (> or =0.4) was 118 +/- 106 days. Receiver operating characteristic (ROC) curves were generated using the sensitivities and specificities of a range of SVPR values for access thrombosis within one, two, three and four months. The areas under the curve (AUCs) for the ROC curves ranged from 0.557 to 0.638, reflecting the absence of SVPR values with both high sensitivity and high specificity for access thrombosis. An increase in SVPR over time was not a better predictor of access thrombosis than absolute SVPR. CONCLUSION: Static venous pressure measurement is not an optimal screening test for identifying AV grafts at risk for thrombosis.