Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial

BACKGROUND: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19. METHODS: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978. FINDINGS: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90. INTERPRETATION: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19. FUNDING: US National Institutes of Health and Operation Warp Speed

Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19

Importance: Therapies that improve survival in critically ill patients with coronavirus disease 2019 (COVID-19) are needed. Tocilizumab, a monoclonal antibody against the interleukin 6 receptor, may counteract the inflammatory cytokine release syndrome in patients with severe COVID-19 illness. Objective: To test whether tocilizumab decreases mortality in this population. Design, Setting, and Participants: The data for this study were derived from a multicenter cohort study of 4485 adults with COVID-19 admitted to participating intensive care units (ICUs) at 68 hospitals across the US from March 4 to May 10, 2020. Critically ill adults with COVID-19 were categorized according to whether they received or did not receive tocilizumab in the first 2 days of admission to the ICU. Data were collected retrospectively until June 12, 2020. A Cox regression model with inverse probability weighting was used to adjust for confounding. Exposures: Treatment with tocilizumab in the first 2 days of ICU admission. Main Outcomes and Measures: Time to death, compared via hazard ratios (HRs), and 30-day mortality, compared via risk differences. Results: Among the 3924 patients included in the analysis (2464 male [62.8%]; median age, 62 [interquartile range {IQR}, 52-71] years), 433 (11.0%) received tocilizumab in the first 2 days of ICU admission. Patients treated with tocilizumab were younger (median age, 58 [IQR, 48-65] vs 63 [IQR, 52-72] years) and had a higher prevalence of hypoxemia on ICU admission (205 of 433 [47.3%] vs 1322 of 3491 [37.9%] with mechanical ventilation and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of <200 mm Hg) than patients not treated with tocilizumab. After applying inverse probability weighting, baseline and severity-of-illness characteristics were well balanced between groups. A total of 1544 patients (39.3%) died, including 125 (28.9%) treated with tocilizumab and 1419 (40.6%) not treated with tocilizumab. In the primary analysis, during a median follow-up of 27 (IQR, 14-37) days, patients treated with tocilizumab had a lower risk of death compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56-0.92). The estimated 30-day mortality was 27.5% (95% CI, 21.2%-33.8%) in the tocilizumab-treated patients and 37.1% (95% CI, 35.5%-38.7%) in the non-tocilizumab–treated patients (risk difference, 9.6%; 95% CI, 3.1%-16.0%). Conclusions and Relevance: Among critically ill patients with COVID-19 in this cohort study, the risk of in-hospital mortality in this study was lower in patients treated with tocilizumab in the first 2 days of ICU admission compared with patients whose treatment did not include early use of tocilizumab. However, the findings may be susceptible to unmeasured confounding, and further research from randomized clinical trials is needed.The writing committee was supported by grants F32HL149337 (Dr. Admon), K23DK120811 (Dr. Srivastava), R01HL085757 (Dr. Parikh), R01HL144566 and R01DK125786 (Dr. Leaf), K12HL138039 (Dr. Donnelly), K23HL130648 (Dr. Mathews), R37AI102634 (Dr. Hernán), F32DC017342 (Dr. Gupta), K08GM134220 and R03AG060179 (Dr. Shaefi), K23HL143053 (Dr. Semler), and R01HL153384 (Dr. Hayek) from the NIH and grant U-M G024231 from the Frankel Cardiovascular Center COVID-19: Impact Research Ignitor (Dr. Hayek)

Association between procalcitonin levels and duration of mechanical ventilation in COVID-19 patients.

BackgroundPatients diagnosed with COVID-19 frequently require mechanical ventilation. Knowledge of laboratory tests associated with the prolonged need for mechanical ventilation may guide resource allocation. We hypothesized that an elevated plasma procalcitonin level (>0.1 ng/ml) would be associated with the duration of invasive mechanical ventilation.MethodsPatients diagnosed with COVID-19, who were admitted to any of our health system's hospitals between March 9th-April 20th, 2020 and required invasive mechanical ventilation, were eligible for this observational cohort study. Demographics, comorbidities, components of the Sequential Organ Failure Assessment score, and procalcitonin levels on admission were obtained from the electronic health record. The primary outcome was the duration of mechanical ventilation; secondary outcomes included 28-day mortality and time to intubation. Outcomes were assessed within the first 28 days of admission. Baseline demographics and comorbidities were summarized by descriptive statistics. Univariate comparisons were made using Pearson's chi-square test for binary outcomes and Mann-Whitney U test for continuous outcomes. A multiple linear regression was fitted to assess the association between procalcitonin levels and the duration of mechanical ventilation.ResultsPatients with an initial procalcitonin level >0.1 ng/ml required a significantly longer duration of mechanical ventilation than patients with a level of ≤0.1 ng/ml (p = 0.021) in the univariate analysis. There was no significant difference in 28-day mortality or time to intubation between the two groups. After adjusted analysis using multivariable linear regression, the duration of mechanical ventilation was, on average, 5.6 (p = 0.016) days longer in patients with an initial procalcitonin level >0.1 ng/ml.ConclusionIn this cohort of 93 mechanically ventilated COVID-19 patients, we found an association between an initial plasma procalcitonin level >0.1 ng/ml and the duration of mechanical ventilation. These findings may help to identify patients at risk for prolonged mechanical ventilation upon admission

Corticosteroid Administration and Impaired Glycemic Control in Mechanically Ventilated COVID-19 Patients

OBJECTIVE: Recent clinical trials confirmed the corticosteroid dexamethasone as an effective treatment for patients with COVID-19 requiring mechanical ventilation. However, limited attention has been given to potential adverse effects of corticosteroid therapy. The objective of this study was to determine the association between corticosteroid administration and impaired glycemic control among COVID-19 patients requiring mechanical ventilation and/or veno-venous extracorporeal membrane oxygenation. DESIGN: Multicenter retrospective cohort study between March 9 and May 17, 2020. The primary outcome was days spent with at least 1 episode of blood glucose either \u3e180 mg/dL or /dL within the first 28 days of admission. SETTING: Twelve hospitals in a United States health system. PATIENTS: Adults diagnosed with COVID-19 requiring invasive mechanical ventilation and/or veno-venous extracorporeal membrane oxygenation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We included 292 mechanically ventilated patients. We fitted a quantile regression model to assess the association between steroid administration ≥320 mg methylprednisolone (equivalent to 60 mg dexamethasone) and impaired glycemic control. Sixty-six patients (22.6%) died within 28 days of intensive care unit admission. Seventy-one patients (24.3%) received a cumulative dose of least 320 mg methylprednisolone equivalents. After adjustment for gender, history of diabetes mellitus, chronic liver disease, sequential organ failure assessment score on intensive care unit day 1, and length of stay, administration of ≥320 mg methylprednisolone equivalent was associated with 4 additional days spent with glucose either /dL or \u3e180 mg/dL (B = 4.00, 95% CI = 2.15-5.85, \u3c .001). CONCLUSIONS: In this cohort study of 292 mechanically ventilated COVID-19 patients, we found an association between corticosteroid administration and higher incidence of both hyperglycemia and hypoglycemia

Association Between Hyperoxia, Supplemental Oxygen, and Mortality in Critically Injured Patients

OBJECTIVES:. Hyperoxia is common among critically ill patients and may increase morbidity and mortality. However, limited evidence exists for critically injured patients. The objective of this study was to determine the association between hyperoxia and in-hospital mortality in adult trauma patients requiring ICU admission. DESIGN, SETTING, AND PARTICIPANTS:. This multicenter, retrospective cohort study was conducted at two level I trauma centers and one level II trauma center in CO between October 2015 and June 2018. All adult trauma patients requiring ICU admission within 24 hours of emergency department arrival were eligible. The primary exposure was oxygenation during the first 7 days of hospitalization. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Primary outcome was in-hospital mortality. Secondary outcomes were hospital-free days and ventilator-free days. We included 3,464 critically injured patients with a mean age of 52.6 years. Sixty-five percent were male, and 66% had blunt trauma mechanism of injury. The primary outcome of in-hospital mortality occurred in 264 patients (7.6%). Of 226,057 patient-hours, 46% were spent in hyperoxia (oxygen saturation > 96%) and 52% in normoxia (oxygen saturation 90–96%). During periods of hyperoxia, the adjusted risk for mortality was higher with greater oxygen administration. At oxygen saturation of 100%, the adjusted risk scores for mortality (95% CI) at Fio2 of 100%, 80%, 60%, and 50% were 6.4 (3.5–11.8), 5.4 (3.4–8.6), 2.7 (1.7–4.1), and 1.5 (1.1–2.2), respectively. At oxygen saturation of 98%, the adjusted risk scores for mortality (95% CI) at Fio2 of 100%, 80%, 60%, and 50% were 7.7 (4.3–13.5), 6.3 (4.1–9.7), 3.2 (2.2–4.8), and 1.9 (1.4–2.7), respectively. CONCLUSIONS:. During hyperoxia, higher oxygen administration was independently associated with a greater risk of mortality among critically injured patients. Level of evidence: Cohort study, level III

Nationwide Clinical Practice Patterns of Anesthesiology Critical Care Physicians-A Survey to Members of the Society of Critical Care Anesthesiologists

BACKGROUNDDespite the growing contributions of critical care anesthesiologists to clinical practice, research, and administrative leadership of intensive care units (ICUs), relatively little is known about the subspecialty-specific clinical practice environment. An understanding of contemporary clinical practice is essential to recognize the opportunities and challenges facing critical care anesthesia, optimize staffing patterns, assess sustainability and satisfaction, and strategically plan for future activity, scope, and training. This study surveyed intensivists who are members of the Society of Critical Care Anesthesiologists (SOCCA) to evaluate practice patterns of critical care anesthesiologists, including compensation, types of ICUs covered, models of overnight ICU coverage, and relationships between these factors. We hypothesized that variability in compensation and practice patterns would be observed between individuals. METHODSBoard-certified critical care anesthesiologists practicing in the United States were identified using the SOCCA membership distribution list and invited to take a voluntary online survey between May and June 2021. Multiple-choice questions with both single- and multiple-select options were used for answers with categorical data, and adaptive questioning was used to clarify stem-based responses. Respondents were asked to describe practice patterns at their respective institutions and provide information about their demographics, salaries, effort in ICUs, as well as other activities. RESULTSA total of 490 participants were invited to take this survey, and 157 (response rate 32%) surveys were completed and analyzed. The majority of respondents were White (73%), male (69%), and younger than 50 years of age (82%). The cardiothoracic/cardiovascular ICU was the most common practice setting, with 69.5% of respondents reporting time working in this unit. Significant variability was observed in ICU practice patterns. Respondents reported spending an equal proportion of their time in clinical practice in the operating rooms and ICUs (median, 40%; interquartile range [IQR], 20%-50%), whereas a smaller proportion-primarily those who completed their training before 2009-reported administrative or research activities. Female respondents reported salaries that were $36,739 less than male respondents; however, this difference was not statistically different, and after adjusting for age and practice type, these differences were less pronounced (-$27,479.79; 95% confidence interval [CI], -$57,232.61 to$2273.03; P = .07). CONCLUSIONSThese survey data provide a current snapshot of anesthesiology critical care clinical practice patterns in the United States. Our findings may inform decision-making around the initiation and expansion of critical care services and optimal staffing patterns, as well as provide a basis for further work that focuses on intensivist satisfaction and burnout

Additional file 3 of Association between treatment failure and hospitalization after receipt of neutralizing monoclonal antibody treatment for COVID-19 outpatients

Additional file 3: Figure S3. Adjusted risk difference and adjusted odds ratio (OR) for treatment failure for each risk factor from a conservative imputation model. In this model, we assumed all missing SARS-CoV-2 positive test dates were ten days prior to the mAb administration date. Risk differences were calculated via Firth's bias-reduced multiple regression logistic regression. Adjusted ORs and 95% confidence intervals (95% CI) were computed by penalized profile likelihood

Additional file 1 of Association between treatment failure and hospitalization after receipt of neutralizing monoclonal antibody treatment for COVID-19 outpatients

Additional file 1: Figure S1. Maximum level of oxygenation support during the index hospitalization for patients who experienced treatment failure. IV: invasive mechanical ventilation; HFC: high flow nasal cannula; NIV: non-invasive ventilation

Additional file 4 of Association between treatment failure and hospitalization after receipt of neutralizing monoclonal antibody treatment for COVID-19 outpatients

Additional file 4: Figure S4. Adjusted risk difference and adjusted odds ratio (OR) for treatment failure for each risk factor from a conservative imputation model. In this model, we included only patients with confirmed dates for both SARS-CoV-2 positive test and mAb administration. Risk differences were calculated via Firth's bias-reduced multiple regression logistic regression. Adjusted ORs and 95% confidence intervals (95% CI) were computed by penalized profile likelihood