Chlorthalidone vs Hydrochlorothiazide for Hypertension Treatment After Myocardial Infarction or Stroke: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Patients with prior myocardial infarction (MI) or stroke have a greater risk of recurrent cardiovascular (CV) events. Objective: To evaluate the association of chlorthalidone (CTD) vs hydrochlorothiazide (HCTZ) with CV outcomes and noncancer deaths in participants with and without prior MI or stroke. Design, Setting, and Participants: This was a prespecified secondary analysis of the Diuretic Comparison Project (DCP), a pragmatic randomized clinical trial conducted within 72 participating Veterans Affairs health care systems from June 2016 to June 2021, in which patients aged 65 years or older with hypertension taking HCTZ at baseline were randomized to continue HCTZ or switch to CTD at pharmacologically comparable doses. This secondary analysis was performed from January 3, 2023, to February 29, 2024. Exposures: Pharmacologically comparable daily dose of HCTZ or CTD and history of MI or stroke. Main Outcomes and Measures: Outcome ascertainment was performed from randomization to the end of the study. The primary outcome consisted of a composite of stroke, MI, urgent coronary revascularization because of unstable angina, acute heart failure hospitalization, or noncancer death. Additional outcomes included achieved blood pressure and hypokalemia (potassium level <3.1 mEq/L; to convert to mmol/L, multiply by 1.0). Results: The DCP randomized 13 523 participants to CTD or HCTZ, with a mean (SD) study duration of 2.4 (1.4) years. At baseline, median age was 72 years (IQR, 69-75 years), and 96.8% were male. Treatment effect was evaluated in subgroups of participants with (n = 1455) and without (n = 12 068) prior MI or stroke at baseline. There was a significant adjusted interaction between treatment group and history of MI or stroke. Participants with prior MI or stroke randomized to CTD had a lower risk of the primary outcome than those receiving HCTZ (105 of 733 [14.3%] vs 140 of 722 [19.4%]; hazard ratio [HR], 0.73; 95% CI, 0.57-0.94; P = .01) compared with participants without prior MI or stroke, among whom incidence of the primary outcome was slightly higher in the CTD arm compared with the HCTZ arm (597 of 6023 [9.9%] vs 535 of 6045 [8.9%]; HR, 1.12; 95% CI, 1.00-1.26; P = .054) (P = .01 for interaction). The incidence of a nadir potassium level less than 3.1 mEq/L and hospitalization for hypokalemia differed among those with and without prior MI or stroke when comparing those randomized to CTD vs HCTZ, with a difference only among those without prior MI or stroke (potassium level <3.1 mEq/L: prior MI or stroke, 43 of 733 [5.9%] vs 37 of 722 [5.1%] [P = .57]; no prior MI or stroke, 292 of 6023 [4.9%] vs 206 of 6045 [3.4%] [P < .001]; hospitalization for hypokalemia: prior MI or stroke, 14 of 733 [1.9%] vs 16 of 722 [2.2%] [P = .72]; no prior MI or stroke: 84 of 6023 [1.4%] vs 57 of 6045 [0.9%] [P = .02]). Conclusions and Relevance: Results of this secondary analysis of the DCP trial suggest that CTD may be associated with reduced major adverse CV events and noncancer deaths in patients with prior MI or stroke compared with HCTZ. Trial Registration: ClinicalTrials.gov Identifier: NCT02185417.

Strategies for secondary use of real-world clinical and administrative data for outcome ascertainment in pragmatic clinical trials.

BACKGROUND: Pragmatic trials are gaining popularity as a cost-effective way to examine treatment effectiveness and generate timely comparative evidence. Incorporating supplementary real-world data is recommended for robust outcome monitoring. However, detailed operational guidelines are needed to inform effective use and integration of heterogeneous databases. OBJECTIVE: Lessons learned from the Veterans Affairs (VA) Diuretic Comparison Project (DCP) are reviewed, providing adaptable recommendations to capture clinical outcomes from real-world data. METHODS: Non-cancer deaths and major cardiovascular (CV) outcomes were determined using VA, Medicare, and National Death Index (NDI) data. Multiple ascertainment strategies were applied, including claims-based algorithms, natural language processing, and systematic chart review. RESULTS: During a mean follow-up of 2.4 (SD = 1.4) years, 907 CV events were identified within the VA healthcare system. Slight delays (∼1 year) were expected in obtaining Medicare data. An additional 298 patients were found having a CV event outside of the VA in 2016 - 2021, increasing the CV event rate from 3.5 % to 5.7 % (770 of 13,523 randomized). NDI data required âˆ¼2 years waiting period. Such inclusion did not increase the number of deaths identified (all 894 deaths were captured by VA data) but enhanced the accuracy in determining cause of death. CONCLUSION: Our experience supports the recommendation of integrating multiple data sources to improve clinical outcome ascertainment. While this approach is promising, hierarchical data aggregation is required when facing different acquisition timelines, information availability/completeness, coding practice, and system configurations. It may not be feasible to implement comparable applications and solutions to studies conducted under different constraints and practice. The recommendations provide guidance and possible action plans for researchers who are interested in applying cross-source data to ascertain all study outcomes.

A Centralized EHR-Based Model for the Recruitment of Rural and Lower Socioeconomic Participants in Pragmatic Trials: A Secondary Analysis of the Diuretic Comparison Project.

Importance: Participant diversity is important for reducing study bias and increasing generalizability of comparative effectiveness research. Objective: Demonstrate the operational efficiency of a centralized electronic health record (EHR)-based model for recruiting difficult-to-reach participants in a pragmatic trial. Design, Setting, and Participants: This comparative effectiveness study was a secondary analysis of Diuretic Comparison Project, a randomized clinical trial conducted between 2016 and 2022 (mean [SD] follow-up, 2.4 [1.4] years) comparing 2 commonly prescribed antihypertensives, which used an EHR-based recruitment model. Electronic study workflows, in tandem with routine clinical practice, were adapted by 72 Veteran Affairs (VA) primary care networks. Data were analyzed from August to December 2022. Main Outcomes and Measures: Measures reflecting recruitment capacity (monthly rate), operational efficiency (median time for completion of electronic procedures), and geographic reach (percentage of patients recruited from rural areas) were examined. Results: A total of 13 523 patients with hypertension (mean [SD] age, 72 [5.4] years; 13 092 male [96.8%]) were recruited from 537 outpatient clinics. Approximately 205 patients were randomized per month and a median of 35 days (Q1-Q3, 23-80 days) was needed to complete electronic recruitment. The annual income was below the national median for 69% of the cohort. Patients from all 50 states, Puerto Rico, and the District of Columbia were included and 45% resided in rural areas. Conclusions and Relevance: In this secondary analysis of a multicenter pragmatic trial, a centralized EHR-based recruitment model was associated with improved participation from underrepresented groups. These participants often are difficult to reach, with their exclusion potentially biasing trial results; eliminating in-person study visits and local site involvement can minimize barriers for the recruitment of patients from rural and lower socioeconomic areas. Trial Registration: The Diuretic Comparison Project (DCP) was registered on ClinicalTrials.gov Identifier: NCT02185417.

Temperature Changes During Electrophysiology Ablation in Veterans and 1-Year Success Rates: A Retrospective Pilot Analysis.

OBJECTIVES: The authors hypothesized that body core temperature during cardiac arrhythmia procedures in the electrophysiology laboratory declines, and examined the association of changes with the patient or procedural factors. They hypothesized that a greater degree of change negatively affects 1-year ablation success. DESIGN: Retrospective observational study. SETTING: Veteran's Administration Boston Healthcare System. PARTICIPANTS: Consecutive records of veterans undergoing ablation procedures under general anesthesia. INTERVENTIONS: Retrospective data collection and analysis from the electronic medical record. MEASUREMENTS AND MAIN RESULTS: Patient and procedural characteristics were collected from the electronic medical record. Core temperature data included baseline (BT) (following entry to the care process on the day of the procedure), the start (ST) and end of the procedure temperatures (ET), and their differences. The 1-year ablation success was assessed as described elsewhere in the literature. The authors used the paired t-test, linear, and logistic regression for hypothesis testing. Among 107 veterans, core temperatures were significantly lower between BT and ST, BT and ET, and ST and ET (p < 0.001 for all). One-year ablation success was 74.8% (n = 80). In multivariate logistic regression adjusted for age, body mass index and BTs showed a greater degree of change from BT to ET, and the ST-to-ET temperature was significantly associated with lower odds of success (odds ratios of 0.57 and 0.42, respectively; p < 0.05 for both). CONCLUSIONS: Core temperature declines during ablation. Greater temperature decline during general anesthesia was associated with lower 1-year ablation success rates.

Ascertainment of stroke from administrative data to support a pragmatic embedded clinical trial.

The goal of this observational study was to identify stroke hospitalizations using International Classification of Disease (ICD)-10 codes and use these codes to develop an ascertainment algorithm for use in pragmatic clinical trials, reducing or eliminating the need for manual chart adjudication in future. Using VA (Veterans Affairs) electronic medical records, 9959 patient charts with ICD-10 codes indicating stroke were screened and a sample of 304 were adjudicated by three clinical reviewers. Hospitalizations were categorized as stroke or non-stroke and positive predictive value (PPV) was calculated for each ICD-10 code that was sampled. The adjudicated codes were categorized for use in a decision tool for identifying stroke in a clinical trial. Of the 304 hospitalizations adjudicated, 192 met the definition of stroke. Of the ICD-10 codes evaluated, I61 yielded the highest PPV (100%) while I63.x yielded the 2nd highest PPV (90%) with a false discovery rate of 10%. A relatively high PPV of ≥80% was associated with codes I60.1-7, I61, I62.9 and I63, which accounted for nearly half of all cases reviewed. Hospitalizations associated with these codes were categorized at positive stroke cases. The incorporation of large administrative datasets, and elimination of trial specific data collection, increases efficiencies, while reducing costs. Accurate algorithms must be developed to allow for identification of clinical endpoints from administrative databases to offer a reliable alternative to study-specific case report form completion. This study demonstrates an example of how to apply medical record data to a decision tool for clinical trial outcomes. CSP597 or clinicaltrials.gov NCT02185417.

Telephone informed consent in a pragmatic point-of-care clinical trial embedded in primary care.

BACKGROUND: One benefit of pragmatic clinical trials is reduction of the burden on patients and clinical staff while facilitating a learning healthcare system. One way to decrease the work of clinical staff is through decentralized telephone consent. METHODS: The Diuretic Comparison Project (DCP) was a nationwide Point of Care pragmatic clinical trial conducted by the VA Cooperative Studies Program. The purpose of the trial was to compare the clinical effectiveness on major CV outcomes of two commonly used diuretics, hydrochlorothiazide and chlorthalidone, in an elderly patient population. Telephone consent was allowed for this study because of its minimal risk designation. Telephone consent was more difficult than initially anticipated and the study team constantly adjusted methods to find timely solutions. RESULTS: The major challenges can be categorized as call center-related, telecommunications, operational, and study population based. In particular, the possible technical and operational pitfalls are rarely discussed. By presenting hurdles here, future studies may avoid these challenges and start studies with a more effective system in place. CONCLUSIONS: DCP is a novel study designed to answer an important clinical question. The lessons learned from implementing a centralized call center for the Diuretic Comparison Project helped the study reach enrollment goals and develop a centralized telephone consent system that can be utilized for future pragmatic and explanatory clinical trials. CLINICAL TRIAL REGISTRATION: The study is registered on ClinicalTrials.gov; NCT02185417 [https://clinicaltrials.gov/ct2/show/NCT02185417]. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

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

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

Practical issues in pragmatic trials: the implementation of the Diuretic Comparison Project.

BACKGROUND/AIMS: The US Department of Veterans Affairs Point of Care Clinical Trial Program conducts studies that utilize informatics infrastructure to integrate clinical trial protocols into routine care delivery. The Diuretic Comparison Project compared hydrochlorothiazide to chlorthalidone in reduction of major cardiovascular events in subjects with hypertension. Here we describe the cultural, technical, regulatory, and logistical challenges and solutions that enabled successful implementation of this large pragmatic comparative effectiveness Point of Care clinical trial. METHODS: Patients were recruited from 72 Veterans Affairs Healthcare Systems using centralized processes for subject identification, obtaining informed consent, data collection, safety monitoring, site communication, and endpoint identification with minimal perturbation of the local clinical care ecosystem. Patients continued to be managed exclusively by their clinical care providers without protocol specified study visits, treatment recommendations, or data collection extraneous to routine care. Centralized study processes were operationalized through the application layer of the electronic health record via a data coordinating center staffed by clinical nurses, data scientists, and statisticians without site-based research coordinators. Study data was collected from the Veterans Affairs electronic health record supplemented by Medicare and National Death Index data. RESULTS: The study exceeded its enrolled goal (13,523 subjects) and followed subjects for the 5-year study duration. The key determinant of program success was collaboration between researchers, regulators, clinicians, and administrative staff at the site level to customize study procedures to align with local clinical practice. This flexibility was enabled by designation of the study as minimal risk and determination that clinical care providers were not engaged in research by the Veterans Affairs Central Institutional Review Board. Cultural, regulatory, technical, and logistical problems were identified and solved through iterative collaboration between clinical and research entities. Paramount among these problems was customization of the Veterans Affairs electronic health record and data systems to accommodate study procedures. CONCLUSIONS: Leveraging clinical care for large-scale clinical trials is feasible but requires a rethinking of traditional clinical trial design (and regulation) to better meet requirements of clinical care ecosystems. Study designs must accommodate site-specific practice variation to reduce the impact on clinical care. A tradeoff thus exists between designing trial processes tailored to expedite local study implementation versus those to produce a more refined response to the research question. The availability of a uniform and flexible electronic health record in the Department of Veterans Affairs played a major role in the success of the trial. Conducting Point of Care research in other healthcare systems without such research-friendly infrastructure presents a more formidable challenge.

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.

Chlorthalidone vs. Hydrochlorothiazide for Hypertension-Cardiovascular Events.

BACKGROUND: Whether chlorthalidone is superior to hydrochlorothiazide for preventing major adverse cardiovascular events in patients with hypertension is unclear. METHODS: In a pragmatic trial, we randomly assigned adults 65 years of age or older who were patients in the Department of Veterans Affairs health system and had been receiving hydrochlorothiazide at a daily dose of 25 or 50 mg to continue therapy with hydrochlorothiazide or to switch to chlorthalidone at a daily dose of 12.5 or 25 mg. The primary outcome was a composite of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and non-cancer-related death. Safety was also assessed. RESULTS: A total of 13,523 patients underwent randomization. The mean age was 72 years. At baseline, hydrochlorothiazide at a dose of 25 mg per day had been prescribed in 12,781 patients (94.5%). The mean baseline systolic blood pressure in each group was 139 mm Hg. At a median follow-up of 2.4 years, there was little difference in the occurrence of primary-outcome events between the chlorthalidone group (702 patients [10.4%]) and the hydrochlorothiazide group (675 patients [10.0%]) (hazard ratio, 1.04; 95% confidence interval, 0.94 to 1.16; P = 0.45). There were no between-group differences in the occurrence of any of the components of the primary outcome. The incidence of hypokalemia was higher in the chlorthalidone group than in the hydrochlorothiazide group (6.0% vs. 4.4%, P<0.001). CONCLUSIONS: In this large pragmatic trial of thiazide diuretics at doses commonly used in clinical practice, patients who received chlorthalidone did not have a lower occurrence of major cardiovascular outcome events or non-cancer-related deaths than patients who received hydrochlorothiazide. (Funded by the Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT02185417.).

Increased residual cardiovascular risk in U.S. veterans with moderately-elevated baseline triglycerides and well-controlled LDL-C levels on statins.

Background: Recent studies have demonstrated a causal role for elevated triglycerides (TG) in incident cardiovascular (CV) events in patients with established coronary heart disease (CHD) and those with CV risk factors alone, particularly diabetes. Objective: Using a large cohort of U.S. veterans with statin-controlled LDL-C levels (40-100 mg/dL), we explored residual CV risk among patients with elevated baseline TG levels (150-499 mg/dL) vs. those with normal TG levels (<150 mg/dL). Methods: We identified veterans receiving a statin but not a TG-lowering agent from the VA electronic health records database, from 2010 to 2015. We compared composite CV event rates (MI, stroke, unstable angina, coronary revascularization, and CV death) between the elevated TG and normal TG groups. We stratified the study cohort according to 3 CV risk groups: (1) no diabetes and no prior CV event, (2) diabetes and no prior CV event, and (3) prior CV event. We calculated crude event rates, rate ratios, and event rate ratios adjusted for age, sex, systolic blood pressure, estimated glomerular filtration rate, and weight. Results: The cohort included 396,189 veterans (predominantly male and white) of whom 109,195 (28%) had elevated TG levels. Those with elevated TG were younger (age 73 vs. 77 years) and had a higher body mass index (31.3 vs. 28.3 Kg/M2). The overall composite crude and adjusted rate ratios comparing the elevated and normal TG groups were 1.10 (1.09, 1.12) and 1.05 (1.03, 1.06), respectively. For CV risk groups 1, 2 and 3, the adjusted rate ratios comparing the elevated and normal TG groups were 0.99 (0.96, 1.02), 1.05 (1.02, 1.08), and 1.07 (1.04, 1.10), respectively. An association of increased rate ratios did not hold for fatal events. Conclusion: Those with elevated TG levels and well-controlled LDL-C on statins showed a modest increase in CV events compared to those with normal TG. Elevated TG levels were associated with increased CV events in patients with established CV disease and with diabetes only, suggesting that elevated TG levels are associated with a similar degree of residual risk in high-risk primary prevention and secondary prevention settings.

Design of a pragmatic clinical trial embedded in the Electronic Health Record: The VA's Diuretic Comparison Project.

BACKGROUND: Recent US guidelines recommend chlorthalidone over other thiazide-type diuretics for the treatment of hypertension based on its long half-life and proven ability to reduce CVD events. Despite recommendations most clinicians prescribe hydrochlorothiazide (HCTZ) over chlorthalidone (CTD). No randomized controlled data exist comparing these two diuretics on cardiovascular outcomes. METHODS: The Diuretic Comparison Project (DCP) is a multicenter, two-arm, parallel, Prospective Randomized Open, Blinded End-point (PROBE) trial testing the primary hypothesis that CTD is superior to HCTZ in the prevention of non-fatal CVD events and non-cancer death. Patients with hypertension taking HCTZ 25 or 50 mg were randomly assigned to either continue their current HCTZ or switch to an equipotent dose of CTD. The primary outcome is time to the first occurrence of a composite outcome consisting of a non-fatal CVD event (stroke, myocardial infarction, urgent coronary revascularization because of unstable angina, or hospitalization for acute heart failure) or non-cancer death. The trial randomized 13,523 patients at 72 VA medical centers. The study is conducted by a centralized research team with site procedures embedded in the electronic health record and all data collected through administrative claims data, with no study related visits for participants. The trial will have 90% power to detect an absolute reduction in the composite event rate of 2.4%. RESULTS: Enrollment ended in November 2021. There are 4128 participting primary care providers and 16,595 patients individually consented to participate, 13,523 of whom were randomized. CONCLUSIONS: DCP should provide much needed evidence as to whether CTD is superior to HCTZ in preventing cardiovascular events in hypertensive patients. CLINICAL TRIAL REGISTRATION: NCT02185417 [https://clinicaltrials.gov/ct2/show/NCT02185417].

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.

Rapid implementation of a modular clinical trial informatics solution for COVID-19 research.

Veterans Health Administration (VHA) services are most frequently used by patients 65 years and older, an age group that is disproportionally affected by COVID-19. Here we describe a modular Clinical Trial Informatics Solution (CTIS) that was rapidly developed and deployed to support a multi-hospital embedded pragmatic clinical trial in COVID-19 patients within the VHA. Our CTIS includes tools for patient eligibility screening, informed consent tracking, treatment randomization, EHR data transformation for reporting and interfaces for patient outcome and adverse event tracking. We hope our CTIS component descriptions and practical lessons learned will serve as a useful building block for others creating their own clinical trial tools and have made application and database code publicly available.

ProjectFlow: a configurable workflow management application for point of care research.

OBJECTIVE: To best meet our point-of-care research (POC-R) needs, we developed ProjectFlow, a configurable, clinical research workflow management application. In this article, we describe ProjectFlow and how it is used to manage study processes for the Diuretic Comparison Project (DCP) and the Research Precision Oncology Program (RePOP). MATERIALS AND METHODS: The Veterans Health Administration (VHA) is the largest integrated health care system in the United States. ProjectFlow is a flexible web-based workflow management tool specifically created to facilitate conduct of our clinical research initiatives within the VHA. The application was developed using the Grails web framework and allows researchers to create custom workflows using Business Process Model and Notation. RESULTS: As of January 2021, ProjectFlow has facilitated management of study recruitment, enrollment, randomization, and drug orders for over 10 000 patients for the DCP clinical trial. It has also helped us evaluate over 3800 patients for recruitment and enroll over 370 of them into RePOP for use in data sharing partnerships and predictive analytics aimed at optimizing cancer treatment in the VHA. DISCUSSION: The POC-R study design embeds research processes within day-to-day clinical care and leverages longitudinal electronic health record (EHR) data for study recruitment, monitoring, and outcome reporting. Software that allows flexibility in study workflow creation and integrates with enterprise EHR systems is critical to the success of POC-R. CONCLUSIONS: We developed a flexible web-based informatics solution called ProjectFlow that supports custom research workflow configuration and has ability to integrate data from existing VHA EHR systems.

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.

Prevalence and Risk Factors for CKD in the General Population of Southwestern Nicaragua.

BACKGROUND: Studies have described Mesoamerican nephropathy among agricultural workers of El Salvador and northwestern Nicaragua. Data on prevalence and risk factors for CKD beyond agricultural workers and in other regions in Nicaragua are sparse. METHODS: We recruited participants from 32 randomly selected communities in the Department of Rivas's ten municipalities in two phases. In phase 1, we screened participants using a field-based capillary creatinine measuring system and collected self-reported information on lifestyle and occupational, exposure, and health histories. Two years later, in phase 2, we enrolled 222 new participants, performing serum creatinine testing in these participants and confirmatory serum creatinine testing in phase 1 participants. RESULTS: We enrolled 1242 of 1397 adults (89%) living in 533 households (median age 41 years; 43% male). We confirmed CKD (eGFR<60 ml/min per 1.73 m2) in 53 of 1227 (4.3%) evaluable participants. In multivariable testing, risk factors for prevalent CKD included age (odds ratio [OR], 1.92; 95% confidence interval [95% CI], 1.89 to 1.96) and self-reported history of hypertension (OR, 1.95; 95% CI, 1.04 to 3.64), diabetes (OR, 2.88; 95% CI, 1.40 to 5.93), or current or past work in the sugarcane industry (OR 2.92; 95% CI, 1.36 to 6.27). CONCLUSIONS: Adjusted CKD prevalence was about 5% with repeat confirmatory testing in southwest Nicaragua, lower than in the northwest region. Risk factors included diabetes, hypertension, and current or prior work in the sugarcane industry but not in other forms of agricultural work. Formal CKD surveillance programs in Nicaragua are needed to assess the overall burden of CKD nationally, with a focus on agricultural workers.

A Novel Method to Combine Assessment of Benefit and Harm: Outcome Measures in Rheumatology 3×3 Methodology Applied to Two Active Comparator Trials.

OBJECTIVE: The Outcome Measures in Rheumatology (OMERACT) 3×3 method analyzes the occurrence of benefit and harm simultaneously at the individual patient level. We applied this method to 2 recent rheumatoid arthritis (RA) trial data sets. METHODS: The Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) and the Rheumatoid Arthritis Comparison of Active Therapies (RACAT) randomized trial outcomes for safety were defined according to OMERACT as having no adverse events (AEs), non-serious AEs, and serious AEs. Treatment efficacy was defined as good, moderate, or no response. A good treatment response without any AEs was labeled an unqualified success, and no treatment response but at least 1 AE was considered an unmitigated failure. The association between benefit and harm was assessed by chi-square or exact tests, as appropriate. RESULTS: In TEAR, 612 of 755 patients had response data at 48 weeks: 14% of patients experienced unqualified success and 9% had unmitigated failure, with no difference between the treatment arms. Treatment response and AE rates were not correlated. In RACAT, 309 of 353 patients had response data at 48 weeks: 6% of patients experienced unqualified success and 11% had unmitigated failure, with no differences between the treatment arms. Response and AE rates were negatively correlated. The frequency of AEs and serious AEs increased as response decreased (P = 0.008). CONCLUSION: We found some evidence that clinical response may be reduced by the co-occurrence of AEs.