Target Trial Emulation: A Framework for Causal Inference From Observational Data.

This Guide to Statistics and Methods describes the use of target trial emulation to design an observational study so it preserves the advantages of a randomized clinical trial, points out the limitations of the method, and provides an example of its use.

Characterizing modifications to a comparative effectiveness research study: the OPTIMIZE trial-using the Framework for Reporting Adaptations and Modifications to Evidence-based Interventions (FRAME).

BACKGROUND: The OPTIMIZE trial is a multi-site, comparative effectiveness research (CER) study that uses a Sequential Multiple Assessment Randomized Trial (SMART) designed to examine the effectiveness of complex health interventions (cognitive behavioral therapy, physical therapy, and mindfulness) for adults with chronic low back pain. Modifications are anticipated when implementing complex interventions in CER. Disruptions due to COVID have created unanticipated challenges also requiring modifications. Recent methodologic standards for CER studies emphasize that fully characterizing modifications made is necessary to interpret and implement trial results. The purpose of this paper is to outline the modifications made to the OPTIMIZE trial using the Framework for Reporting Adaptations and Modifications to Evidence-Based Interventions (FRAME) to characterize modifications to the OPTIMIZE trial in response to the COVID pandemic and other challenges encountered. METHODS: The FRAME outlines a strategy to identify and report modifications to evidence-based interventions or implementation strategies, whether planned or unplanned. We use the FRAME to characterize the process used to modify the aspects of the OPTIMIZE trial. Modifications were made to improve lower-than-anticipated rates of treatment initiation and COVID-related restrictions. Contextual modifications were made to permit telehealth delivery of treatments originally designed for in-person delivery. Training modifications were made with study personnel to provide more detailed information to potential participants, use motivational interviewing communication techniques to clarify potential participants' motivation and possible barriers to initiating treatment, and provide greater assistance with scheduling of assigned treatments. RESULTS: Modifications were developed with input from the trial's patient and stakeholder advisory panels. The goals of the modifications were to improve trial feasibility without compromising the interventions' core functions. Modifications were approved by the study funder and the trial steering committee. CONCLUSIONS: Full and transparent reporting of modifications to clinical trials, whether planned or unplanned, is critical for interpreting the trial's eventual results and considering future implementation efforts. TRIAL REGISTRATION: ClinicalTrials.gov NCT03859713. Registered on March 1, 2019.

ISPE-Endorsed Guidance in Using Electronic Health Records for Comparative Effectiveness Research in COVID-19: Opportunities and Trade-Offs.

As the scientific research community along with healthcare professionals and decision makers around the world fight tirelessly against the coronavirus disease 2019 (COVID-19) pandemic, the need for comparative effectiveness research (CER) on preventive and therapeutic interventions for COVID-19 is immense. Randomized controlled trials markedly under-represent the frail and complex patients seen in routine care, and they do not typically have data on long-term treatment effects. The increasing availability of electronic health records (EHRs) for clinical research offers the opportunity to generate timely real-world evidence reflective of routine care for optimal management of COVID-19. However, there are many potential threats to the validity of CER based on EHR data that are not originally generated for research purposes. To ensure unbiased and robust results, we need high-quality healthcare databases, rigorous study designs, and proper implementation of appropriate statistical methods. We aimed to describe opportunities and challenges in EHR-based CER for COVID-19-related questions and to introduce best practices in pharmacoepidemiology to minimize potential biases. We structured our discussion into the following topics: (1) study population identification based on exposure status; (2) ascertainment of outcomes; (3) common biases and potential solutions; and (iv) data operational challenges specific to COVID-19 CER using EHRs. We provide structured guidance for the proper conduct and appraisal of drug and vaccine effectiveness and safety research using EHR data for the pandemic. This paper is endorsed by the International Society for Pharmacoepidemiology (ISPE).

Early Patient-Centered Outcomes Research Experience With the Use of Telehealth to Address Disparities: Scoping Review.

BACKGROUND: Health systems and providers across America are increasingly employing telehealth technologies to better serve medically underserved low-income, minority, and rural populations at the highest risk for health disparities. The Patient-Centered Outcomes Research Institute (PCORI) has invested US $386 million in comparative effectiveness research in telehealth, yet little is known about the key early lessons garnered from this research regarding the best practices in using telehealth to address disparities. OBJECTIVE: This paper describes preliminary lessons from the body of research using study findings and case studies drawn from PCORI seminal patient-centered outcomes research (PCOR) initiatives. The primary purpose was to identify common barriers and facilitators to implementing telehealth technologies in populations at risk for disparities. METHODS: A systematic scoping review of telehealth studies addressing disparities was performed. It was guided by the Arksey and O'Malley Scoping Review Framework and focused on PCORI's active portfolio of telehealth studies and key PCOR identified by study investigators. We drew on this broad literature using illustrative examples from early PCOR experience and published literature to assess barriers and facilitators to implementing telehealth in populations at risk for disparities, using the active implementation framework to extract data. Major themes regarding how telehealth interventions can overcome barriers to telehealth adoption and implementation were identified through this review using an iterative Delphi process to achieve consensus among the PCORI investigators participating in the study. RESULTS: PCORI has funded 89 comparative effectiveness studies in telehealth, of which 41 assessed the use of telehealth to improve outcomes for populations at risk for health disparities. These 41 studies employed various overlapping modalities including mobile devices (29/41, 71%), web-based interventions (30/41, 73%), real-time videoconferencing (15/41, 37%), remote patient monitoring (8/41, 20%), and store-and-forward (ie, asynchronous electronic transmission) interventions (4/41, 10%). The studies targeted one or more of PCORI's priority populations, including racial and ethnic minorities (31/41, 41%), people living in rural areas, and those with low income/low socioeconomic status, low health literacy, or disabilities. Major themes identified across these studies included the importance of patient-centered design, cultural tailoring of telehealth solutions, delivering telehealth through trusted intermediaries, partnering with payers to expand telehealth reimbursement, and ensuring confidential sharing of private information. CONCLUSIONS: Early PCOR evidence suggests that the most effective health system- and provider-level telehealth implementation solutions to address disparities employ patient-centered and culturally tailored telehealth solutions whose development is actively guided by the patients themselves to meet the needs of specific communities and populations. Further, this evidence shows that the best practices in telehealth implementation include delivery of telehealth through trusted intermediaries, close partnership with payers to facilitate reimbursement and sustainability, and safeguards to ensure patient-guided confidential sharing of personal health information.

Comparative Effectiveness of an Automated Text Messaging Service for Monitoring COVID-19 at Home.

BACKGROUND: Although most patients with SARS-CoV-2 infection can be safely managed at home, the need for hospitalization can arise suddenly. OBJECTIVE: To determine whether enrollment in an automated remote monitoring service for community-dwelling adults with COVID-19 at home ("COVID Watch") was associated with improved mortality. DESIGN: Retrospective cohort analysis. SETTING: Mid-Atlantic academic health system in the United States. PARTICIPANTS: Outpatients who tested positive for SARS-CoV-2 between 23 March and 30 November 2020. INTERVENTION: The COVID Watch service consists of twice-daily, automated text message check-ins with an option to report worsening symptoms at any time. All escalations were managed 24 hours a day, 7 days a week by dedicated telemedicine clinicians. MEASUREMENTS: Thirty- and 60-day outcomes of patients enrolled in COVID Watch were compared with those of patients who were eligible to enroll but received usual care. The primary outcome was death at 30 days. Secondary outcomes included emergency department (ED) visits and hospitalizations. Treatment effects were estimated with propensity score-weighted risk adjustment models. RESULTS: A total of 3488 patients enrolled in COVID Watch and 4377 usual care control participants were compared with propensity score weighted models. At 30 days, COVID Watch patients had an odds ratio for death of 0.32 (95% CI, 0.12 to 0.72), with 1.8 fewer deaths per 1000 patients (CI, 0.5 to 3.1) (P = 0.005); at 60 days, the difference was 2.5 fewer deaths per 1000 patients (CI, 0.9 to 4.0) (P = 0.002). Patients in COVID Watch had more telemedicine encounters, ED visits, and hospitalizations and presented to the ED sooner (mean, 1.9 days sooner [CI, 0.9 to 2.9 days]; all P < 0.001). LIMITATION: Observational study with the potential for unobserved confounding. CONCLUSION: Enrollment of outpatients with COVID-19 in an automated remote monitoring service was associated with reduced mortality, potentially explained by more frequent telemedicine encounters and more frequent and earlier presentation to the ED. PRIMARY FUNDING SOURCE: Patient-Centered Outcomes Research Institute.

Odds of Testing Positive for SARS-CoV-2 Following Receipt of 3 vs 2 Doses of the BNT162b2 mRNA Vaccine.

Importance: With the evidence of waning immunity of the mRNA vaccine BNT162b2 (Pfizer-BioNTech), a nationwide third-dose (booster) vaccination campaign was initiated in Israel during August 2021; other countries have begun to administer a booster shot as well. Objective: To evaluate the initial short-term additional benefit of a 3-dose vs a 2-dose regimen against infection of SARS-CoV-2. Design, Setting, and Participants: This preliminary retrospective case-control study used 2 complementary approaches: a test-negative design and a matched case-control design. Participants were included from the national centralized database of Maccabi Healthcare Services, an Israeli healthcare maintenance organization covering 2.5 million members. Data were collected between March 1, 2020, and October 4, 2021, and analyses focused on the period from August 1, 2021, to October 4, 2021, because the booster dose was widely administered from August 1 onward. Exposures: Either 2 doses or 3 doses of the BNT162b2 vaccine. Main Outcomes and Measures: The reduction in the odds of a positive SARS-CoV-2 polymerase chain reaction (PCR) test at different time intervals following receipt of the booster dose (0-6, 7-13, 14-20, 21-27, and 28-65 days) compared with receiving only 2 doses. Results: The study population included 306 710 members of Maccabi Healthcare Services who were 40 years and older (55% female) and received either 2 or 3 doses of the BNT162b2 vaccine and did not have a positive PCR test result for SARS-CoV-2 prior to the start of the follow-up period. During this period, there were 500 232 PCR tests performed, 227 380 among those who received 2 doses and 272 852 among those who received 3 doses, with 14 989 (6.6%) and 4941 (1.8%) positive test results in each group, respectively. Comparing those who received a booster and those who received 2 doses, there was an estimated odds ratio of 0.14 (95% CI, 0.13-0.15) 28 to 65 days following receipt of the booster (86% reduction in the odds of testing positive for SARS-CoV-2). Conclusion and Relevance: Previous studies have demonstrated that vaccine-derived protection against SARS-CoV-2 wanes over time. In this case-control analysis, we showed an association between receipt of the booster dose and a reduction in the odds of testing positive for SARS-CoV-2, potentially counteracting waning immunity in the short term. Further monitoring of data from this population is needed to determine the duration of immunity following the booster.

Electronic Health Record Network Research in Infectious Diseases.

With the marked increases in electronic health record (EHR) use for providing clinical care, there have been parallel efforts to leverage EHR data for research. EHR repositories offer the promise of vast amounts of clinical data not easily captured with traditional research methods and facilitate clinical epidemiology and comparative effectiveness research, including analyses to identify patients at higher risk for complications or who are better candidates for treatment. These types of studies have been relatively slow to penetrate the field of infectious diseases, but the need for rapid turnaround during the COVID-19 global pandemic has accelerated the uptake. This review discusses the rationale for her network projects, opportunities and challenges that such networks present, and some prior studies within the field of infectious diseases.

Early clinical trial data and real-world assessment of COVID-19 vaccines: Insights from the Society of Infectious Diseases Pharmacists.

As of August 2021, there were three COVID-19 vaccines available in the United States for the prevention of coronavirus 2019 (COVID-19). The purpose of this narrative review is to examine the early experience from the Emergency Use Authorization (EUA) of BNT162b2 (Pfizer, Inc./BioNTech), mRNA-1273 (Moderna, Inc.), and Ad26.COV2.S (Johnson and Johnson/Janssen Global Services, LLC) through July 2021. The EUA data from the clinical trials have largely been corroborated by real-world effectiveness investigations post-authorization. These studies indicate that immunity is obtained within 2 weeks post-vaccination and may endure for 6 months. The immunity conferred by the vaccines may also be effective against SARS-CoV-2 variants of concern. Additionally, populations not included in the emergency use authorization studies may also benefit from vaccination. This look back at the initial clinical experience can be used by the global community to inform and develop COVID-19 vaccine programs.

Protocol refinement for a diabetes pragmatic trial using the PRECIS-2 framework.

BACKGROUND: This report describes how we refined a protocol for a pragmatic comparative effectiveness study of two models of an evidence-based diabetes shared medical appointment intervention and used the PRECIS-2 rating system to evaluate these adaptations. METHODS: We report primary data collected between June and August 2019, and protocol refinements completed between 2018 and 2020. Twenty-two members of the study team collaborated in protocol refinement and completed the PRECIS-2 ratings of study pragmatism. We discuss study design refinements made to achieve the desired level of pragmatism vs. experimental control for each of the nine PRECIS-2 dimensions. Study team members received training on PRECIS-2 scoring and were asked to rate the study protocol on the nine PRECIS-2 dimensions. Ratings were compared using descriptive statistics. RESULTS: In general, the PRECIS-2 ratings revealed high levels of pragmatism, but somewhat less pragmatic ratings on the categories of Delivery and Organization (costs and resources). This variation was purposeful, and we provide the rationale for and steps taken to obtain the targeted level of pragmatism on each PRECIS-2 dimension, as well as detail design changes made to a) make the design more pragmatic and b) address COVID-19 issues. There was general agreement among team members and across different types of stakeholders on PRECIS-2 ratings. CONCLUSIONS: We discuss lessons learned from use of PRECIS-2 and experiences in refining the study to be maximally pragmatic on some dimensions and less so on other dimensions. This paper expands on prior research by describing actions to achieve higher levels of pragmatism and revise our protocol fit to the changed context. We make recommendations for future use of PRECIS-2 to help address changing context and other strategies for the planning of and transparent reporting on pragmatic research and comparative effectiveness research. TRIAL REGISTRATION: Clinicaltrials.gov Registration ID: NCT03590041 .

Quantifying Viral Particle Aerosolization Risk During Tracheostomy Surgery and Tracheostomy Care.

Importance: During respiratory disease outbreaks such as the COVID-19 pandemic, aerosol-generating procedures, including tracheostomy, are associated with the risk of viral transmission to health care workers. Objective: To quantify particle aerosolization during tracheostomy surgery and tracheostomy care and to evaluate interventions that minimize the risk of viral particle exposure. Design, Setting, and Participants: This comparative effectiveness study was conducted from August 2020 to January 2021 at a tertiary care academic institution. Aerosol generation was measured in real time with an optical particle counter during simulated (manikin) tracheostomy surgical and clinical conditions, including cough, airway nebulization, open suctioning, and electrocautery. Aerosol sampling was also performed during in vivo swine tracheostomy procedures (n = 4), with or without electrocautery. Fluorescent dye was used to visualize cough spread onto the surgical field during swine tracheostomy. Finally, 6 tracheostomy coverings were compared with no tracheostomy covering to quantify reduction in particle aerosolization. Main Outcomes and Measures: Respirable aerosolized particle concentration. Results: Cough, airway humidification, open suctioning, and electrocautery produced aerosol particles substantially above baseline. Compared with uncovered tracheostomy, decreased aerosolization was found with the use of tracheostomy coverings, including a cotton mask (73.8% [(95% CI, 63.0%-84.5%]; d = 3.8), polyester gaiter 79.5% [95% CI, 68.7%-90.3%]; d = 7.2), humidification mask (82.8% [95% CI, 72.0%-93.7%]; d = 8.6), heat moisture exchanger (HME) (91.0% [95% CI, 80.2%-101.7%]; d = 19.0), and surgical mask (89.9% [95% CI, 79.3%-100.6%]; d = 12.8). Simultaneous use of a surgical mask and HME decreased the particle concentration compared with either the HME (95% CI, 1.6%-12.3%; Cohen d = 1.2) or surgical mask (95% CI, 2.7%-13.2%; d = 1.9) used independently. Procedures performed with electrocautery increased total aerosolized particles by 1500 particles/m3 per 5-second interval (95% CI, 1380-1610 particles/m3 per 5-second interval; d = 1.8). Conclusions and Relevance: The findings of this laboratory and animal comparative effectiveness study indicate that tracheostomy surgery and tracheostomy care are associated with significant aerosol generation, putting health care workers at risk for viral transmission of airborne diseases. Combined HME and surgical mask coverage of the tracheostomy was associated with decreased aerosolization, thereby reducing the risk of viral transmission to health care workers.

Comparison of Actual Performance in the Flow and Fraction of Inspired O2 among Different High-Flow Nasal Cannula Devices: A Bench Study.

Background: High-flow nasal cannula (HFNC) oxygen therapy has been recommended for use in coronavirus disease 2019 (COVID-19) patients with acute respiratory failure and many other clinical conditions. HFNC devices produced by different manufacturers may have varied performance. Whether there is a difference in these devices and the extent of the differences in performance remain unknown. Methods: Four HFNC devices (AIRVO 2, TNI softFlow 50, HUMID-BH, and OH-70C) and a ventilator with an HFNC module (bellavista 1000) were evaluated. The flow was set at 20, 25, 30, 35, 40, 45, 50, 60, 70, and 80 L/min, and the FiO2 was set at 21%, 26%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, and 90%. Then, one side of the cannulas was clipped to simulate the compression, bending, or blocking of the nasal cannulas. The flow and FiO2 of the delivered gas were recorded and compared among settings and devices. Results: The actual-flow and actual-FiO2 delivered by different settings and devices varied. AIRVO 2 had superior performance in flow and FiO2 accuracy. bellavista 1000 and OH-70C had good performance in the accuracy of actual-flows and actual-FiO2, respectively. bellavista 1000 and HUMID-BH had a larger flow range from 10 to 80 L/min, but only bellavista 1000 could provide a stable flow with an excessive resistance up to 60 L/min. TNI softFlow 50 had the best flow compensation and could provide sufficient flow with excessive resistance at 20-50 L/min. Conclusions: The variation in flow, FiO2 settings, and devices could influence the actual-flow and actual-FiO2 delivered. AIRVO 2 and OH-70C showed better FiO2 accuracy. TNI softFlow 50, bellavista 1000, and HUMID-BH could lower the risk of insufficient flow support due to accidental compression or blocking of the cannulas. In addition, ventilators with HFNC modules provided comparable flow and FiO2 and could be an alternative to standalone HFNC devices.

Community Health Worker Asthma Interventions for Children: Results From a Clinically Integrated Randomized Comparative Effectiveness Trial (2016‒2019).

Objectives. To compare asthma control for children receiving either community health worker (CHW) or certified asthma educator (AE-C) services. Methods. The Asthma Action at Erie Trial is a comparative effectiveness trial that ran from 2016 to 2019 in Cook County, Illinois. Participants (aged 5‒16 years with uncontrolled asthma) were randomized to 10 home visits from clinically integrated asthma CHWs or 2 in-clinic sessions from an AE-C. Results. Participants (n = 223) were mainly Hispanic (85%) and low-income. Both intervention groups showed significant improvement in asthma control scores over time. Asthma control was maintained after interventions ended. The CHW group experienced a greater improvement in asthma control scores. One year after intervention cessation, the CHW group had a 42% reduction in days of activity limitation relative to the AE-C group (b = 0.58; 95% confidence interval = 0.35, 0.96). Conclusions. Both interventions were associated with meaningful improvements in asthma control. Improvements continued for 1 year after intervention cessation and were stronger with the CHW intervention. Public Health Implications. Clinically integrated asthma CHW and AE-C services that do not provide home environmental remediation equipment may improve and sustain asthma control.

Assessment of Effectiveness of 1 Dose of BNT162b2 Vaccine for SARS-CoV-2 Infection 13 to 24 Days After Immunization.

Importance: The BNT162b2 vaccine showed high efficacy against COVID-19 in a phase III randomized clinical trial. A vaccine effectiveness evaluation in a real-world setting is needed. Objective: To assess the short-term effectiveness of the first dose of the BNT162b2-vaccine against SARS-CoV-2 infection 13 to 24 days after immunization in a real-world setting. Design, Setting, and Participants: This comparative effectiveness study used data from a 2.6 million-member state-mandated health care system in Israel. Participants included all individuals aged 16 years and older who received 1 dose of the BNT162b2 vaccine between December 19, 2020, and January 15, 2021. Data were analyzed in March 2021. Exposure: Receipt of 1 dose of the BNT162b2 vaccine. Main Outcomes and Measures: Information was collected regarding medical history and positive SARS-CoV-2 polymerase chain reaction test and COVID-19 symptoms from 1 day after first vaccine to January 17, 2021. Daily and cumulative infection rates in days 13 to 24 were compared with days 1 to 12 after the first dose using Kaplan-Meier survival analysis and generalized linear models. Results: Data for 503 875 individuals (mean [SD] age, 59.7 [14.7] years; 263 228 [52.4%] women) were analyzed, of whom 351 897 had follow-up data for days 13 to 24. The cumulative incidence of SARS-CoV-2 infection was 2484 individuals (0.57%) during days 1 through 12 and 614 individuals (0.27%) in days 13 through 24. The weighted mean (SE) daily incidence of SARS-CoV-2 infection in days 1 through 12 was 43.41 (12.07) infections per 100 000 population and 21.08 (6.16) infections per 100 000 population in days 13 through 24, a relative risk reduction (RRR) of 51.4% (95% CI, 16.3%-71.8%). The decrease in incidence was evident from day 18 after the first dose. Similar RRRs were calculated in individuals aged 60 years or older (44.5%; 95% CI, 4.1%-67.9%), those younger than 60 years (50.2%; 95% CI, 14.1%-71.2%), women (50.0%; 95% CI, 13.5%-71.0%), and men (52.1%; 95% CI, 17.3%-72.2%). Findings were similar in subpopulations (eg, ultraorthodox Jewish: RRR, 53.5% [95% CI, 19.2%-73.2%]) and patients with various comorbidities (eg, cardiovascular diseases: RRR, 47.2% [95% CI, 7.8%-69.8%]). Vaccine effectiveness against symptomatic COVID-19 was 54.4% (95% CI, 21.4%-73.6%). Conclusions and Relevance: In this comparative effectiveness study of a single dose of the BNT162b2 vaccine, results were comparable to that of the phase III randomized clinical trial.

Assessment of Simulated SARS-CoV-2 Infection and Mortality Risk Associated With Radiation Therapy Among Patients in 8 Randomized Clinical Trials.

Importance: During the COVID-19 pandemic, cancer therapy may put patients at risk of SARS-CoV-2 infection and mortality. The impacts of proposed alternatives on reducing infection risk are unknown. Objective: To investigate how the COVID-19 pandemic is associated with the risks and benefits of standard radiation therapy (RT). Design, Setting, and Participants: This comparative effectiveness study used estimated individual patient-level data extracted from published Kaplan-Meier survival figures from 8 randomized clinical trials across oncology from 1993 to 2014 that evaluated the inclusion of RT or compared different RT fractionation regimens. Included trials were Dutch TME and TROG 01.04 examining rectal cancer; CALGB 9343, OCOG hypofractionation trial, FAST-Forward, and NSABP B-39 examining early stage breast cancer, and CHHiP and HYPO-RT-PC examining prostate cancer. Risk of SARS-CoV-2 infection and mortality associated with receipt of RT in the treatment arms were simulated and trials were reanalyzed. Data were analyzed between April 1, 2020, and June 30, 2020. Exposures: COVID-19 risk associated with treatment was simulated across different pandemic scenarios, varying infection risk per fractions (IRFs) and case fatality rates (CFRs). Main Outcomes and Measures: Overall survival was evaluated using Cox proportional hazards modeling under different pandemic scenarios. Results: Estimated IPLD from a total of 14 170 patients were included in the simulations. In scenarios with low COVID-19-associated risks (IRF, 0.5%; CFR, 5%), fractionation was not significantly associated with outcomes. In locally advanced rectal cancer, short-course RT was associated with better outcomes than long-course chemoradiation (TROG 01.04) and was associated with similar outcomes as RT omission (Dutch TME) in most settings (eg, TROG 01.04 median HR, 0.66 [95% CI, 0.46-0.96]; Dutch TME median HR, 0.91 [95% CI, 0.80-1.03] in a scenario with IRF 5% and CFR 20%). Moderate hypofractionation in early stage breast cancer (OCOG hypofractionation trial) and prostate cancer (CHHiP) was not associated with survival benefits in the setting of COVID-19 (eg, OCOG hypofractionation trial median HR, 0.89 [95% CI, 0.74-1.06]; CHHiP median HR, 0.87 [95% CI, 0.75-1.01] under high-risk scenario with IRF 10% and CFR 30%). More aggressive hypofractionation (FAST-Forward, HYPO-RT-PC) and accelerated partial breast irradiation (NSABP B-39) were associated with improved survival in higher risk scenarios (eg, FAST-Forward median HR, 0.58 [95% CI, 0.49-0.68]; HYPO-RT-PC median HR, 0.60 [95% CI, 0.48-0.75] under scenario with IRF 10% and CFR 30%). Conclusions and Relevance: In this comparative effectiveness study of data from 8 clinical trials of patients receiving radiation therapy to simulate COVID-19 risk and mortality rates, treatment modification was not associated with altered risk from COVID-19 in lower-risk scenarios and was only associated with decreased mortality in very high COVID-19-risk scenarios. This model, which can be adapted to dynamic changes in COVID-19 risk, provides a flexible, quantitative approach to assess the potential impact of treatment modifications and supports the continued delivery of standard evidence-based care with appropriate precautions against COVID-19.

Comparison of Time to Clinical Improvement With vs Without Remdesivir Treatment in Hospitalized Patients With COVID-19.

Importance: Clinical effectiveness data on remdesivir are urgently needed, especially among diverse populations and in combination with other therapies. Objective: To examine whether remdesivir administered with or without corticosteroids for treatment of coronavirus disease 2019 (COVID-19) is associated with more rapid clinical improvement in a racially/ethnically diverse population. Design, Setting, and Participants: This retrospective comparative effectiveness research study was conducted from March 4 to August 29, 2020, in a 5-hospital health system in the Baltimore, Maryland, and Washington, DC, area. Of 2483 individuals with confirmed severe acute respiratory syndrome coronavirus 2 infection assessed by polymerase chain reaction, those who received remdesivir were matched to infected individuals who did not receive remdesivir using time-invariant covariates (age, sex, race/ethnicity, Charlson Comorbidity Index, body mass index, and do-not-resuscitate or do-not-intubate orders) and time-dependent covariates (ratio of peripheral blood oxygen saturation to fraction of inspired oxygen, blood pressure, pulse, temperature, respiratory rate, C-reactive protein level, complete white blood cell count, lymphocyte count, albumin level, alanine aminotransferase level, glomerular filtration rate, dimerized plasmin fragment D [D-dimer] level, and oxygen device). An individual in the remdesivir group with k days of treatment was matched to a control patient who stayed in the hospital at least k days (5 days maximum) beyond the matching day. Exposures: Remdesivir treatment with or without corticosteroid administration. Main Outcomes and Measures: The primary outcome was rate of clinical improvement (hospital discharge or decrease of 2 points on the World Health Organization severity score), and the secondary outcome, mortality at 28 days. An additional outcome was clinical improvement and time to death associated with combined remdesivir and corticosteroid treatment. Results: Of 2483 consecutive admissions, 342 individuals received remdesivir, 184 of whom also received corticosteroids and 158 of whom received remdesivir alone. For these 342 patients, the median age was 60 years (interquartile range, 46-69 years), 189 (55.3%) were men, and 276 (80.7%) self-identified as non-White race/ethnicity. Remdesivir recipients had a shorter time to clinical improvement than matched controls without remdesivir treatment (median, 5.0 days [interquartile range, 4.0-8.0 days] vs 7.0 days [interquartile range, 4.0-10.0 days]; adjusted hazard ratio, 1.47 [95% CI, 1.22-1.79]). Remdesivir recipients had a 28-day mortality rate of 7.7% (22 deaths) compared with 14.0% (40 deaths) among matched controls, but this difference was not statistically significant in the time-to-death analysis (adjusted hazard ratio, 0.70; 95% CI, 0.38-1.28). The addition of corticosteroids to remdesivir was not associated with a reduced hazard of death at 28 days (adjusted hazard ratio, 1.94; 95% CI, 0.67-5.57). Conclusions and Relevance: In this comparative effectiveness research study of adults hospitalized with COVID-19, receipt of remdesivir was associated with faster clinical improvement in a cohort of predominantly non-White patients. Remdesivir plus corticosteroid administration did not reduce the time to death compared with remdesivir administered alone.