Securely sharing DSMB reports to speed decision making from multiple, concurrent, independent studies of similar treatments in COVID-19.

Introduction: As clinical trials were rapidly initiated in response to the COVID-19 pandemic, Data and Safety Monitoring Boards (DSMBs) faced unique challenges overseeing trials of therapies never tested in a disease not yet characterized. Traditionally, individual DSMBs do not interact or have the benefit of seeing data from other accruing trials for an aggregated analysis to meaningfully interpret safety signals of similar therapeutics. In response, we developed a compliant DSMB Coordination (DSMBc) framework to allow the DSMB from one study investigating the use of SARS-CoV-2 convalescent plasma to treat COVID-19 to review data from similar ongoing studies for the purpose of safety monitoring. Methods: The DSMBc process included engagement of DSMB chairs and board members, execution of contractual agreements, secure data acquisition, generation of harmonized reports utilizing statistical graphics, and secure report sharing with DSMB members. Detailed process maps, a secure portal for managing DSMB reports, and templates for data sharing and confidentiality agreements were developed. Results: Four trials participated. Data from one trial were successfully harmonized with that of an ongoing trial. Harmonized reports allowing for visualization and drill down into the data were presented to the ongoing trial's DSMB. While DSMB deliberations are confidential, the Chair confirmed successful review of the harmonized report. Conclusion: It is feasible to coordinate DSMB reviews of multiple independent studies of a similar therapeutic in similar patient cohorts. The materials presented mitigate challenges to DSMBc and will help expand these initiatives so DSMBs may make more informed decisions with all available information.

Assessment of Awake Prone Positioning in Hospitalized Adults With COVID-19: A Nonrandomized Controlled Trial.

Importance: Awake prone positioning may improve hypoxemia among patients with COVID-19, but whether it is associated with improved clinical outcomes remains unknown. Objective: To determine whether the recommendation of awake prone positioning is associated with improved outcomes among patients with COVID-19-related hypoxemia who have not received mechanical ventilation. Design, Setting, and Participants: This pragmatic nonrandomized controlled trial was conducted at 2 academic medical centers (Vanderbilt University Medical Center and NorthShore University HealthSystem) during the COVID-19 pandemic. A total of 501 adult patients with COVID-19-associated hypoxemia who had not received mechanical ventilation were enrolled from May 13 to December 11, 2020. Interventions: Patients were assigned 1:1 to receive either the practitioner-recommended awake prone positioning intervention (intervention group) or usual care (usual care group). Main Outcomes and Measures: Primary outcome analyses were performed using a bayesian proportional odds model with covariate adjustment for clinical severity ranking based on the World Health Organization ordinal outcome scale, which was modified to highlight the worst level of hypoxemia on study day 5. Results: A total of 501 patients (mean [SD] age, 61.0 [15.3] years; 284 [56.7%] were male; and most [417 (83.2%)] were self-reported non-Hispanic or non-Latinx) were included. Baseline severity was comparable between the intervention vs usual care groups, with 170 patients (65.9%) vs 162 patients (66.7%) receiving oxygen via standard low-flow nasal cannula, 71 patients (27.5%) vs 62 patients (25.5%) receiving oxygen via high-flow nasal cannula, and 16 patients (6.2%) vs 19 patients (7.8%) receiving noninvasive positive-pressure ventilation. Nursing observations estimated that patients in the intervention group spent a median of 4.2 hours (IQR, 1.8-6.7 hours) in the prone position per day compared with 0 hours (IQR, 0-0.7 hours) per day in the usual care group. On study day 5, the bayesian posterior probability of the intervention group having worse outcomes than the usual care group on the modified World Health Organization ordinal outcome scale was 0.998 (posterior median adjusted odds ratio [aOR], 1.63; 95% credibility interval [CrI], 1.16-2.31). However, on study days 14 and 28, the posterior probabilities of harm were 0.874 (aOR, 1.29; 95% CrI, 0.84-1.99) and 0.673 (aOR, 1.12; 95% CrI, 0.67-1.86), respectively. Exploratory outcomes (progression to mechanical ventilation, length of stay, and 28-day mortality) did not differ between groups. Conclusions and Relevance: In this nonrandomized controlled trial, prone positioning offered no observed clinical benefit among patients with COVID-19-associated hypoxemia who had not received mechanical ventilation. Moreover, there was substantial evidence of worsened clinical outcomes at study day 5 among patients recommended to receive the awake prone positioning intervention, suggesting potential harm. Trial Registration: ClinicalTrials.gov Identifier: NCT04359797.

Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial.

Importance: Data on the efficacy of hydroxychloroquine for the treatment of coronavirus disease 2019 (COVID-19) are needed. Objective: To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19. Design, Setting, and Participants: This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients. Interventions: Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237). Main Outcomes and Measures: The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality. Results: Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, -0.2% [95% CI, -5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09]). Conclusions and Relevance: Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults. Trial Registration: ClinicalTrials.gov: NCT04332991.