Care of the Seriously Ill Patient with SARS-CoV-2.

In late 2019, SARS-CoV-2 caused the greatest global health crisis in a century, impacting all aspects of society. As the COVID-19 pandemic evolved throughout 2020 and 2021, multiple variants emerged, contributing to multiple surges in cases of COVID-19 worldwide. In 2021, highly effective vaccines became available, although the pandemic continues into 2022. There has been tremendous expansion of basic, translational, and clinical knowledge about SARS-CoV-2 and COVID-19 since the pandemic's onset. Treatment options have been rapidly explored, attempting to repurpose preexisting medications in tandem with development and evaluation of novel agents. Care of the seriously ill patient is examined.

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.

Rationale and Design of ORCHID: A Randomized Placebo-controlled Clinical Trial of Hydroxychloroquine for Adults Hospitalized with COVID-19.

The ORCHID (Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients with symptomatic Disease) trial is a multicenter, blinded, randomized trial of hydroxychloroquine versus placebo for the treatment of adults hospitalized with coronavirus disease (COVID-19). This document provides the rationale and background for the trial and highlights key design features. We discuss five novel challenges to the design and conduct of a large, multicenter, randomized trial during a pandemic, including 1) widespread, off-label use of the study drug before the availability of safety and efficacy data; 2) the need to adapt traditional procedures for documentation of informed consent during an infectious pandemic; 3) developing a flexible and robust Bayesian analysis incorporating significant uncertainty about the disease, outcomes, and treatment; 4) obtaining indistinguishable drug and placebo without delaying enrollment; and 5) rapidly obtaining administrative and regulatory approvals. Our goals in describing how the ORCHID trial progressed from study conception to enrollment of the first patient in 15 days are to inform the development of other high-quality, multicenter trials targeting COVID-19. We describe lessons learned to improve the efficiency of future clinical trials, particularly in the setting of pandemics. The ORCHID trial will provide high-quality, clinically relevant data on the safety and efficacy of hydroxychloroquine for the treatment of COVID-19 among hospitalized adults.Clinical trial registered with www.clinicaltrials.gov (NCT04332991).

Hydroxychloroquine versus Azithromycin for Hospitalized Patients with Suspected or Confirmed COVID-19 (HAHPS). Protocol for a Pragmatic, Open-Label, Active Comparator Trial

Coronavirus disease (COVID-19) is a potentially fatal illness with no proven therapy beyond excellent supportive care. Treatments are urgently sought. Adaptations to traditional trial logistics and design to allow rapid implementation, evaluation of trials within a global trials context, flexible interim monitoring, and access outside traditional research hospitals (even in settings where formal placebos are unavailable) may be helpful. Thoughtful adaptations to traditional trial designs, especially within the global context of related studies, may also foster collaborative relationships among government, community, and the research enterprise. Here, we describe the protocol for a pragmatic, active comparator trial in as many as 300 patients comparing two current "off-label" treatments for COVID-19-hydroxychloroquine and azithromycin-in academic and nonacademic hospitals in Utah. We developed the trial in response to local pressures for widespread, indiscriminate off-label use of these medications. We used a hybrid Bayesian-frequentist design for interim monitoring to allow rapid, contextual assessment of the available evidence. We also developed an inference grid for interpreting the range of possible results from this trial within the context of parallel trials and prepared for a network meta-analysis of the resulting data. This trial was prospectively registered (ClinicalTrials.gov Identifier: NCT04329832) before enrollment of the first patient.Clinical trial registered with www.clinicaltrials.gov (NCT04329832).