Using a novel in-mask non-invasive ventilator microphone to improve talker intelligibility in healthy and hospitalised adults.

Purpose: Non-invasive ventilation (NIV) provides respiratory support without invasive endotracheal intubation but can hinder patients' ability to communicate effectively. The current study presents preliminary results using a novel in-mask ventilator microphone to enhance talker intelligibility while receiving NIV.Method: A proof-of-concept study assessed sentence intelligibility of five healthy adult talkers using a prototype model of the microphone under continuous positive airway pressure (CPAP; 5/5 cm H2O) and bilevel positive airway pressure (BiPAP; 8/4 cm H2O) ventilator conditions. A pilot study then assessed intelligibility, subjective comprehensibility and naturalness, and patient- and conversation partner-reported communication outcomes for eight patients undergoing therapeutic NIV while being treated in an intensive care unit (ICU).Result: Intelligibility increased significantly with the microphone on in the BiPAP condition for healthy volunteers. For patients undergoing NIV in an ICU, intelligibility, comprehensibility, and patient and conversation partner ratings of conversation satisfaction significantly improved with the microphone on. Patients with lower baselines without the microphone in certain measures (intelligibility, comprehensibility) generally showed a greater microphone benefit than patients with higher baselines.Conclusion: Use of a novel microphone integrated into NIV improved intelligibility during ventilation for both healthy volunteers and patients undergoing therapeutic NIV. Additional clinical studies will define precise benefits and implications of such improved intelligibility.

Implementation of coordinated spontaneous awakening and breathing trials using telehealth-enabled, real-time audit and feedback for clinician adherence (TEACH): a type II hybrid effectiveness-implementation cluster-randomized trial.

BACKGROUND: Intensive care unit (ICU) patients on mechanical ventilation often require sedation and analgesia to improve comfort and decrease pain. Prolonged sedation and analgesia, however, may increase time on mechanical ventilation, risk for ventilator associated pneumonia, and delirium. Coordinated interruptions in sedation [spontaneous awakening trials (SATs)] and spontaneous breathing trials (SBTs) increase ventilator-free days and improve mortality. Coordination of SATs and SBTs is difficult with substantial implementation barriers due to difficult-to-execute sequencing between nurses and respiratory therapists. Telehealth-enabled remote care has the potential to overcome these barriers and improve coordinated SAT and SBT adherence by enabling proactive high-risk patient monitoring, surveillance, and real-time assistance to frontline ICU teams. METHODS: The telehealth-enabled, real-time audit and feedback for clinician adherence (TEACH) study will determine whether adding a telehealth augmented real-time audit and feedback to a usual supervisor-led audit and feedback intervention will yield higher coordinated SAT and SBT adherence and more ventilator-free days in mechanically ventilated patients than a usual supervisor-led audit and feedback intervention alone in a type II hybrid effectiveness-implementation cluster-randomized clinical trial in 12 Intermountain Health hospitals with 15 ICUs. In the active comparator control group (six hospitals), the only intervention is the usual supervisor-led audit and feedback implementation. The telehealth-enabled support (TEACH) intervention in six hospitals adds real-time identification of patients eligible for a coordinated SAT and SBT and consultative input from telehealth respiratory therapists, nurses, and physicians to the bedside clinicians to promote adherence including real-time assistance with execution. All intubated and mechanically ventilated patients ≥ 16 years of age are eligible for enrollment except for patients who die on the day of intubation or have preexisting brain death. Based on preliminary power analyses, we plan a 36-month intervention period that includes a 90-day run-in period. Estimated enrollment in the final analysis is up to 9900 mechanically ventilated patients over 33 months. DISCUSSION: The TEACH study will enhance implementation science by providing insight into how a telehealth intervention augmenting a usual audit and feedback implementation may improve adherence to coordinated SAT and SBT and increase ventilator-free days. TRIAL REGISTRATION: Clinicaltrials.gov, NCT05141396 , registered 12/02/2021.

Modifiable in-hospital factors for 12-month global cognition, post-traumatic stress disorder symptoms, and depression symptoms in adults hospitalized with COVID-19.

BACKGROUND: We sought to identify potentially modifiable in-hospital factors associated with global cognition, post-traumatic stress disorder (PTSD) symptoms, and depression symptoms at 12 months. METHODS: This was a multi-center prospective cohort study in adult hospitalized patients with acute COVID-19. The following in-hospital factors were assessed: delirium; frequency of in-person and virtual visits by friends and family; and hydroxychloroquine, corticosteroid, and remdesivir administration. Twelve-month global cognition was characterized by the MOCA-Blind. Twelve-month PTSD and depression were characterized using the PTSD Checklist for the DSM-V and Hospital Anxiety Depression Scale, respectively. FINDINGS: Two hundred three patients completed the 12-month follow-up assessments. Remdesivir use was associated with significantly higher cognition at 12 months based on the MOCA-Blind (adjusted odds ratio [aOR] = 1.98, 95% CI: 1.06, 3.70). Delirium was associated with worsening 12-month PTSD (aOR = 3.44, 95% CI: 1.89, 6.28) and depression (aOR = 2.18, 95% CI: 1.23, 3.84) symptoms. Multiple virtual visits per day during hospitalization was associated with lower 12-month depression symptoms compared to those with less than daily virtual visits (aOR = 0.40, 95% CI: 0.19, 0.85). CONCLUSION: Potentially modifiable factors associated with better long-term outcomes included remdesivir use (associated with better cognitive function), avoidance of delirium (associated with less PTSD and depression symptoms), and increased virtual interactions with friends and family (associated with less depression symptoms).

Awakening and Breathing Coordination: A Mixed-Methods Analysis of Determinants of Implementation.

Rationale: Routine spontaneous awakening and breathing trial coordination (SAT/SBT) improves outcomes for mechanically ventilated patients, but adherence varies. Understanding barriers to and facilitators of consistent daily use of SAT/SBT (implementation determinants) can guide the development of implementation strategies to increase adherence to these evidence-based interventions. Objectives: We conducted an explanatory, sequential mixed-methods study to measure variation in the routine daily use of SAT/SBT and to identify implementation determinants that might explain variation in SAT/SBT use across 15 intensive care units (ICUs) in urban and rural locations within an integrated, community-based health system. Methods: We described the patient population and measured adherence to daily use of coordinated SAT/SBT from January to June 2021, selecting four sites with varied adherence levels for semistructured field interviews. We conducted key informant interviews with critical care nurses, respiratory therapists, and physicians/advanced practice clinicians (n = 55) from these four sites between October and December 2021 and performed content analysis to identify implementation determinants of SAT/SBT use. Results: The 15 sites had 1,901 ICU admissions receiving invasive mechanical ventilation (IMV) for ⩾24 hours during the measurement period. The mean IMV patient age was 58 years, and the median IMV duration was 5.3 days (interquartile range, 2.5-11.9). Coordinated SAT/SBT adherence (within 2 h) was estimated at 21% systemwide (site range, 9-68%). ICU clinicians were generally familiar with SAT/SBT but varied in their knowledge and beliefs about what constituted an evidence-based SAT/SBT. Clinicians reported that SAT/SBT coordination was difficult in the context of existing ICU workflows, and existing protocols did not explicitly define how coordination should be performed. The lack of an agreed-upon system-level measure for tracking daily use of SAT/SBT led to uncertainty regarding what constituted adherence. The effects of the COVID-19 pandemic increased clinician workloads, impacting performance. Conclusions: Coordinated SAT/SBT adherence varied substantially across 15 ICUs within an integrated, community-based health system. Implementation strategies that address barriers identified by this study, including knowledge deficits, challenges regarding workflow coordination, and the lack of performance measurement, should be tested in future hybrid implementation-effectiveness trials to increase adherence to daily use of coordinated SAT/SBT and minimize harm related to the prolonged use of mechanical ventilation and sedation.

Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial.

BACKGROUND: There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure. METHODS: TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761. FINDINGS: Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10). INTERPRETATION: Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy. FUNDING: National Institutes of Health.

Implementation of Lung-Protective Ventilation in Patients With Acute Respiratory Failure.

OBJECTIVES: We implemented a computerized protocol for low tidal volume ventilation (LTVV) to improve management and outcomes of mechanically ventilated patients with, and without, the acute respiratory distress syndrome (ARDS). DESIGN: Pragmatic, nonrandomized stepped wedge type II hybrid implementation/effectiveness trial. SETTING: Twelve hospitals in an integrated healthcare system over a 2-year period. PATIENTS: Patients greater than or equal to 18 years old who had initiation of mechanical ventilation in the emergency department or ICU. We excluded patients who died or transitioned to comfort care on the day of admission to the ICU. We defined a subgroup of patients with ARDS for analysis. INTERVENTIONS: Implementation of ventilator protocols for LTVV in the ICU. MEASUREMENTS AND MAIN RESULTS: Our primary clinical outcome was ventilator-free days (VFDs) to day 28. Our primary process outcome was median initial set tidal volume. We included 8,692 mechanically ventilated patients, 3,282 (38%) of whom had ARDS. After implementation, set tidal volume reported as mL/kg predicted body weight decreased from median 6.1 mL/kg (interquartile range [IQR], 6.0-6.8 mL/kg) to 6.0 mL/kg (IQR, 6.0-6.6 mL/kg) ( p = 0.009). The percent of patients receiving LTVV (tidal volume ≤ 6.5 mL/kg) increased from 69.8% ( n = 1,721) to 72.5% ( n = 1,846) ( p = 0.036) after implementation. The percent of patients receiving greater than 8 mL/kg initial set tidal volume was reduced from 9.0% ( n = 222) to 6.7% ( n = 174) ( p = 0.005) after implementation. Among patients with ARDS, day 1 positive end-expiratory pressure increased from 6.7 to 8.0 cm H 2 O ( p < 0.001). We observed no difference in VFD (adjusted odds ratio, 1.06; 95% CI, 0.91-1.24; p = 0.44), or in secondary outcomes of length of stay or mortality, either within the main cohort or the subgroup of patients with ARDS. CONCLUSIONS: We observed improved adherence to optimal ventilator management with implementation of a computerized protocol and reduction in the number of patients receiving tidal volumes greater than 8 mL/kg. We did not observe improvement in clinical outcomes.

Delivery of Lung-protective Ventilation for Acute Respiratory Distress Syndrome: A Hybrid Implementation-Effectiveness Trial.

Rationale: Lung-protective ventilation (LPV) improves outcomes for patients with acute respiratory distress syndrome (ARDS), but adherence remains inadequate. Objectives: To measure the process and clinical impacts of implementation of a science-based intervention to improve LPV adherence for patients with ARDS, in part by increased use of clinical decision support (CDS). Methods: We conducted a type III hybrid implementation/effectiveness pilot trial enrolling adult patients with ARDS admitted to three hospitals before and after the launch of a multimodal implementation intervention to increase the use of mechanical ventilation CDS and improve LPV adherence. The primary outcome was patients' percentage of time adherent to low tidal volume (⩽6.5 ml/kg predicted body weight) ventilation (LTVV). Secondary outcomes included adherence to prescribed oxygenation settings, the use of the CDS tool's independent oxygenation and ventilation components, ventilator-free days, and mortality. Analyses employed multivariable regression to compare adjusted pre- versus postintervention outcomes after the exclusion of a postintervention wash-in period. A sensitivity analysis measured process outcomes' level and trend change postintervention using segmented regression. Results: The 446 included patients had a mean age of 60 years, and 43% were female. Demographic and clinical characteristics were similar pre- versus postintervention. The adjusted proportion of adherent time increased postintervention for LTVV (9.2%; 95% confidence interval [CI], 3.8-14.5%) and prescribed oxygenation settings (11.9%; 95% CI, 7.2-16.5%), as did the probability patients spent ⩾90% of ventilated time on LTVV (adjusted odds ratio [aOR] 2.58; 95% CI, 1.64-4.10) and use of ventilation CDS (aOR, 41.3%; 95% CI, 35.9-46.7%) and oxygenation CDS (aOR, 54.3%; 95% CI, 50.9-57.7%). Ventilator-free days (aOR, 1.15; 95% CI, 0.81-1.62) and 28-day mortality (aOR, 0.78; 95% CI, 0.50-1.20) did not change significantly after intervention. Segmented regression analysis supported a causal relationship between the intervention and improved CDS usage but suggested trends before intervention rather than the studied intervention could explain increased LPV adherence after the intervention. Conclusions: In this pilot trial, a multimodal implementation intervention was associated with increased use of ventilator management CDS for patients with ARDS but was not associated with differences in clinical outcomes and may not have independently caused the observed postintervention improvements in LPV adherence. Clinical trial registered with www.clinicaltrials.gov (NCT03984175).

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.

Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19 : A Randomized Controlled Trial.

BACKGROUND: Ensovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection. OBJECTIVE: To investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone. DESIGN: Double-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978). SETTING: Multinational, multicenter trial. PARTICIPANTS: Adults hospitalized with COVID-19. INTERVENTION: Intravenous ensovibep, 600 mg, or placebo. MEASUREMENTS: Ensovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home or place of usual residence after hospital discharge. A composite safety outcome that included death, serious adverse events, end-organ disease, and serious infections was assessed through day 90. RESULTS: An independent data and safety monitoring board recommended that enrollment be halted for early futility after 485 patients were randomly assigned and received an infusion of ensovibep (n = 247) or placebo (n = 238). The odds ratio (OR) for a more favorable pulmonary outcome in the ensovibep (vs. placebo) group at day 5 was 0.93 (95% CI, 0.67 to 1.30; P = 0.68; OR > 1 would favor ensovibep). The 90-day cumulative incidence of sustained recovery was 82% for ensovibep and 80% for placebo (subhazard ratio [sHR], 1.06 [CI, 0.88 to 1.28]; sHR > 1 would favor ensovibep). The primary composite safety outcome at day 90 occurred in 78 ensovibep participants (32%) and 70 placebo participants (29%) (HR, 1.07 [CI, 0.77 to 1.47]; HR < 1 would favor ensovibep). LIMITATION: The trial was prematurely stopped because of futility, limiting power for the primary outcome. CONCLUSION: Compared with placebo, ensovibep did not improve clinical outcomes for hospitalized participants with COVID-19 receiving standard care, including remdesivir; no safety concerns were identified. PRIMARY FUNDING SOURCE: National Institutes of Health.

New-Onset Systemic Capillary Leak Syndrome in an Adult Patient with COVID-19.

Systemic capillary leak syndrome (SCLS) is a rare disorder manifesting as shock, hemoconcentration, and hypoalbuminemia, which may be either idiopathic or secondary to an underlying disease process. We report a case of an adult with COVID-19 infection associated with new onset SCLS. Our case joins only two other cases of new SCLS associated with COVID-19 infection reported in the literature. The clinical and laboratory findings in this case are distinct from findings seen in COVID-19 cytokine storm syndrome. Whether our therapeutic approach was efficacious is unknown. Further research into causes and therapies for these syndromes is urgently indicated.

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.

Hydroxychloroquine vs. Azithromycin for Hospitalized Patients with COVID-19 (HAHPS): Results of a Randomized, Active Comparator Trial.

RATIONALE: The COVID-19 pandemic struck an immunologically naïve, globally interconnected population. In the face of a new infectious agent causing acute respiratory failure for which there were no known effective therapies, rapid, often pragmatic trials were necessary to evaluate potential treatments, frequently starting with medications that are already marketed for other indications. Early in the pandemic, hydroxychloroquine and azithromycin were two such candidates. OBJECTIVE: Assess the relative efficacy of hydroxychloroquine and azithromycin among hospitalized patients with COVID-19. METHODS: We performed a randomized clinical trial of hydroxychloroquine vs. azithromycin among hospitalized patients with COVID-19. Treatment was 5 days of study medication. The primary endpoint was the COVID Ordinal Outcomes scale at day 14. Secondary endpoints included hospital-, ICU-, and ventilator-free days at day 28. The trial was stopped early after enrollment of 85 patients when a separate clinical trial concluded that a clinically important effect of hydroxychloroquine over placebo was definitively excluded. Comparisons were made a priori using a proportional odds model from a Bayesian perspective. RESULTS: We enrolled 85 patients at 13 hospitals over 11 weeks. Adherence to study medication was high. The estimated odds ratio for less favorable status on the ordinal scale for hydroxychloroquine vs. azithromycin from the primary analysis was 1.07, with a 95% credible interval from 0.63 to 1.83 with a posterior probability of 60% that hydroxychloroquine was worse than azithryomycin. Secondary outcomes displayed a similar, slight preference for azithromycin over hydroxychloroquine. QTc prolongation was rare and did not differ between groups. The twenty safety outcomes were similar between arms with the possible exception of post-randomization onset acute kidney injury, which was more common with hydroxychloroquine (15% vs. 0%). Patients in the hydroxychloroquine arm received remdesivir more often than in the azithromycin arm (19% vs. 2%). There was no apparent association between remdesivir use and acute kidney injury. CONCLUSIONS: While early termination limits the precision of our results, we found no suggestion of substantial efficacy for hydroxychloroquine over azithromycin. Acute kidney injury may be more common with hydroxychloroquine than azithromycin, although this may be due to the play of chance. Differential use of remdesivir may have biased our results in favor of hydroxychloroquine. Our results are consistent with conclusions from other trials that hydroxychloroquine cannot be recommended for inpatients with COVID-19; azithromycin may merit additional investigation. CLINICAL TRIAL REGISTRATION: This trial was prospectively registered (NCT04329832) before enrollment of the first patient.

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).