Anti-SARS-CoV-2 glyco-humanized polyclonal antibody XAV-19: phase II/III randomized placebo-controlled trial shows acceleration to recovery for mild to moderate patients with COVID-19.

Introduction: XAV-19 is a glyco-humanized swine polyclonal antibody targeting SARS-CoV-2 with high neutralizing activity. The safety and clinical efficacy of XAV-19 were investigated in patients with mild to moderate COVID-19. Methods: This phase II/III, multicentric, randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the safety and clinical efficacy of XAV-19 in patients with a seven-point WHO score of 2 to 4 at randomization, i.e., inpatients with COVID-19 requiring or not requiring low-flow oxygen therapy, and outpatients not requiring oxygen (EUROXAV trial, NCT04928430). Adult patients presenting in specialized or emergency units with confirmed COVID-19 and giving their consent to participate in the study were randomized to receive 150 mg of XAV-19 or placebo. The primary endpoint was the proportion of patients with aggravation within 8 days after treatment, defined as a worsening of the seven-point WHO score of at least one point between day 8 and day 1 (inclusion). The neutralization activity of XAV-19 against variants circulating during the trial was tested in parallel. Results: From March 2021 to October 2022, 279 patients received either XAV-19 (N = 140) or placebo (N = 139). A slow enrollment and a low rate of events forced the termination of the premature trial. XAV-19 was well tolerated. Underpowered statistics did not allow the detection of any difference in the primary endpoint between the two groups or in stratified groups. Interestingly, analysis of the time to improvement (secondary endpoint) showed that XAV-19 significantly accelerated the recovery for patients with a WHO score of 2 or 3 (median at 7 days vs. 14 days, p = 0.0159), and even more for patients with a WHO score of 2 (4 days vs. 14 days, p = 0.0003). The neutralizing activity against Omicron and BA.2, BA.2.12.1, BA.4/5, and BQ.1.1 subvariants was shown. Discussion: In this randomized placebo- controlled trial with premature termination, reduction of aggravation by XAV-19 at day 8 in patients with COVID-19 was not detectable. However, a significant reduction of the time to improvement for patients not requiring oxygen was observed. XAV-19 maintained a neutralizing activity against SARS-CoV-2 variants. Altogether, these data support a possible therapeutic interest for patients with mild to moderate COVID-19 requiring anti-SARS-CoV-2 neutralizing antibodies. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT04928430; https://www.clinicaltrialsregister.eu/about.html (EudraCT), identifier 2020-005979-12.

Transitions of blood immune endotypes and improved outcome by anakinra in COVID-19 pneumonia: an analysis of the SAVE-MORE randomized controlled trial.

BACKGROUND: Endotype classification may guide immunomodulatory management of patients with bacterial and viral sepsis. We aimed to identify immune endotypes and transitions associated with response to anakinra (human interleukin 1 receptor antagonist) in participants in the SAVE-MORE trial. METHODS: Adult patients hospitalized with radiological findings of PCR-confirmed severe pneumonia caused by SARS-CoV-2 and plasma-soluble urokinase plasminogen activator receptor levels of ≥ 6 ng/ml in the SAVE-MORE trial (NCT04680949) were characterized at baseline and days 4 and 7 of treatment using a previously defined 33-messenger RNA classifier to assign an immunological endotype in blood. Endpoints were changes in endotypes and progression to severe respiratory failure (SRF) associated with anakinra treatment. RESULTS: At baseline, 23.2% of 393 patients were designated as inflammopathic, 41.1% as adaptive, and 35.7% as coagulopathic. Only 23.9% were designated as the same endotype at days 4 and 7 compared to baseline, while all other patients transitioned between endotypes. Anakinra-treated patients were more likely to remain in the adaptive endotype during 7-day treatment (24.4% vs. 9.9%; p < 0.001). Anakinra also protected patients with coagulopathic endotype at day 7 against SRF compared to placebo (27.8% vs. 55.9%; p = 0.013). CONCLUSION: We identify an association between endotypes defined using blood transcriptome and anakinra therapy for COVID-19 pneumonia, with anakinra-treated patients shifting toward endotypes associated with a better outcome, mainly the adaptive endotype. Trial registration ClinicalTrials.gov, NCT04680949, December 23, 2020.

The Gordian Knot of C. auris: If You Cannot Cut It, Prevent It.

Since its first description in 2009, Candida auris has, so far, resulted in large hospital outbreaks worldwide and is considered an emerging global public health threat. Exceptionally for yeast, it is gifted with a profoundly worrying invasive potential and high inter-patient transmissibility. At the same time, it is capable of colonizing and persisting in both patients and hospital settings for prolonged periods of time, thus creating a vicious cycle of acquisition, spreading, and infection. It exhibits various virulence qualities and thermotolerance, osmotolerance, filamentation, biofilm formation and hydrolytic enzyme production, which are mainly implicated in its pathogenesis. Owing to its unfavorable profile of resistance to diverse antifungal agents and the lack of effective treatment options, the implementation of robust infection prevention and control (IPC) practices is crucial for controlling and minimizing intra-hospital transmission of C. auris. Rapid and accurate microbiological identification, adherence to hand hygiene, use of adequate personal protective equipment (PPE), proper handling of catheters and implantable devices, contact isolation, periodical environmental decontamination, targeted screening, implementation of antimicrobial stewardship (AMS) programs and communication between healthcare facilities about residents' C. auris colonization status are recognized as coherent strategies for preventing its spread. Current knowledge on C. auris epidemiology, clinical characteristics, and its mechanisms of pathogenicity are summarized in the present review and a comprehensive overview of IPC practices ensuring yeast prevention is also provided.

The Burden of COVID-19 in Adult Patients With Hematological Malignancies: A Single-center Experience After the Implementation of Mass-vaccination Programs Against SARS-CoV-2.

BACKGROUND/AIM: Despite the widespread mass-vaccination programs worldwide and the continuing evolution of COVID-19 therapeutics, the burden of SARS-CoV-2 infection in patients with hematological malignancies (HM) remains elusive. The aim of the present study was to assess the clinical characteristics, outcomes and therapeutic strategies applied in HM patients hospitalized during the post-vaccine period in Greece. PATIENTS AND METHODS: From June 2021 to October 2022, 60 HM patients with COVID-19 were retrospectively analyzed. Exploratory end-points included the incidence of intubation, probability of recovery, mortality, and duration of remdesivir (RDV) administration. RESULTS: Overall, mechanical ventilation (MV) was required for five patients and crude mortality was 8.3%. HM of lymphocytic origin (p=0.035) and obesity (p=0.03) were the main determinants of the risk of intubation and among several laboratory markers, only LDH>520 IU/l was proven to be an independent MV predictor (p=0.038). The number of co-existing comorbidities (p=0.05) and disease severity on admission (p<0.001) were found to rule the probability of recovery, and dexamethasone was associated with worse prognosis, particularly in patients with mild/moderate COVID-19. RDV was administered to the entire cohort, of whom 38 were managed with an extended course. In the multivariate analysis, patients with HM of lymphocytic origin were more likely to receive RDV for more than five days (p=0.002). CONCLUSION: Our study emphasizes the frailty of HM patients, even in the era of Omicron-variant predominance, and underlines the need to optimize therapy.

Depression in medical students during the COVID-19 lockdown in Greece.

The COVID-19 pandemic has caused a mental health crisis. The purpose of this study was to estimate the prevalence of depression in medical students in Greece during a nationwide lockdown. The secondary aims were to assess the association of depression with socio-demographic factors and students' attitudes regarding the quality of their studies. The data was gathered anonymously through a self-administered online questionnaire between January 11 and 27, 2021. The CES-D scale was used to measure depression rates. Multiple logistic regression was used to identify factors independently associated with depression. Analyses were conducted using Stata version 16.0 and the IBM® SPSS® software. In total, 978 sixth- and fifth-year medical students participated; their mean age was 23.2 years and 65.6% were females. The prevalence of clinical depression was 21.3% (95% CI: 18.7%, 24.0%), whereas 17.9% (95% CI: 15.5%, 20.4%) experienced severe distress. Depression was more prevalent in females (25.4% vs 13.1% in males, p<0.001). Approximately half (53.4%) of the participants reported a change in plans regarding their medical career due to the pandemic and 16.9% expressed a decreased willingness to practice medicine. Factors independently associated with depression were female gender, living alone or with housemates at high risk for COVID-19, being anxious about becoming infected with SARS-CoV-2, studying in one of the three largest medical schools, negatively evaluating the adjustment of the teaching personnel to online teaching and the university's response to the pandemic. The findings of this study report depression in one out of five medical students during the COVID-19 pandemic, highlighting the need to protect the most vulnerable medical students during a pandemic. Medical students must be able to seek professional mental health services, even in the era of a pandemic. Universities should increase accessibility to support services and provide a student-centered approach in their strategies, as the pandemic has placed a spotlight on an existing phenomenon.

Remdesivir: Effectiveness and Safety in Hospitalized Patients with COVID-19 (ReEs-COVID-19)-Analysis of Data from Daily Practice.

Remdesivir was the first antiviral approved for treating COVID-19. We investigated its patterns of use, effectiveness and safety in clinical practice in Greece. This is a retrospective observational study of hospitalized adults who received remdesivir for COVID-19 in September 2020-February 2021. The main endpoints were the time to recovery (hospital discharge within 30 days from admission) and safety. The "early" (remdesivir initiation within 24 h since hospitalization) and "deferred" (remdesivir initiation later on) groups were compared. One thousand and four patients (60.6% male, mean age 61 years, 74.3% with severe disease, 70.9% with ≥1 comorbidities) were included, and 75.9% of them were on a 5-day regimen, and 86.8% were in the early group. Among those with a baseline mild/moderate disease, the median (95% CI) time to recovery was 8 (7-9) and 12 (11-14) days for the early and deferred groups, respectively (p < 0.001). The corresponding estimates for those with a severe disease were 10 (9-10) and 13 (11-15) days, respectively (p = 0.028). After remdesivir initiation, increased serum transaminases and an acute kidney injury were observed in 6.9% and 2.1%, respectively. Nine (0.9%) patients discontinued the treatment due to adverse events. The effectiveness of remdesivir was increased when it was taken within 24 h since admission regardless of the disease severity. Remdesivir's safety profile is similar to that described in clinical trials and other real-world cohorts.

Dexamethasone attenuates interferon-related cytokine hyperresponsiveness in COVID-19 patients.

Background: Dexamethasone improves the survival of COVID-19 patients in need of supplemental oxygen therapy. Although its broad immunosuppressive effects are well-described, the immunological mechanisms modulated by dexamethasone in patients hospitalized with COVID-19 remain to be elucidated. Objective: We combined functional immunological assays and an omics-based approach to investigate the in vitro and in vivo effects of dexamethasone in the plasma and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients. Methods: Hospitalized COVID-19 patients eligible for dexamethasone therapy were recruited from the general care ward between February and July, 2021. Whole blood transcriptomic and targeted plasma proteomic analyses were performed before and after starting dexamethasone treatment. PBMCs were isolated from healthy individuals and COVID-19 patients and stimulated with inactivated SARS-CoV-2 ex vivo in the presence or absence of dexamethasone and transcriptome and cytokine responses were assessed. Results: Dexamethasone efficiently inhibited SARS-CoV-2-induced in vitro expression of chemokines and cytokines in PBMCs at the transcriptional and protein level. Dexamethasone treatment in COVID-19 patients resulted in down-regulation of genes related to type I and II interferon (IFN) signaling in whole blood immune cells. In addition, dexamethasone attenuated circulating concentrations of secreted interferon-stimulating gene 15 (ISG15) and pro-inflammatory cytokines and chemokines correlating with disease severity and lethal outcomes, such as tumor necrosis factor (TNF), interleukin-6 (IL-6), chemokine ligand 2 (CCL2), C-X-C motif ligand 8 (CXCL8), and C-X-C motif chemokine ligand 10 (CXCL10). In PBMCs from COVID-19 patients that were stimulated ex vivo with multiple pathogens or Toll-like receptor (TLR) ligands, dexamethasone efficiently inhibited cytokine responses. Conclusion: We describe the anti-inflammatory impact of dexamethasone on the pathways contributing to cytokine hyperresponsiveness observed in severe manifestations of COVID-19, including type I/II IFN signaling. Dexamethasone could have adverse effects in COVID-19 patients with mild symptoms by inhibiting IFN responses in early stages of the disease, whereas it exhibits beneficial effects in patients with severe clinical phenotypes by efficiently diminishing cytokine hyperresponsiveness.

Efficacy of Tocilizumab in Severely Ill COVID-19 Patients With Rapid Respiratory Deterioration: A Single Center Experience During the Third Pandemic Wave in Greece.

BACKGROUND/AIM: Immunomodulatory therapy with Tocilizumab (TCZ), a monoclonal antibody against interleukin-6 receptor-alpha, has been endorsed by the World Health Organization and other major regulatory bodies, as part of the standard-of-care therapy for severe or critical COVID-19 cases despite discordant trial outcomes. The aim of the present study was to report the experience of our center regarding TCZ routine use in severely ill COVID-19 patients who were hospitalized during the third pandemic wave in Greece. PATIENTS AND METHODS: From March 2021 to December 2021, we retrospectively analyzed COVID-19 patients with radiological findings of pneumonia and signs of rapid respiratory deterioration that were treated with TCZ. The primary outcome included the risk of intubation or/and death in TCZ-treated patients compared to matched controls. RESULTS: TCZ administration was neither predictive of intubation and/or death [OR=17.5 (95% CI=0.47-652.2; p=0.12)] or associated with fewer events (p=0.92) in multivariate analysis. CONCLUSION: Our single-center real-life experience is in line with recently published research, revealing no benefit from TCZ routine use in severely or critically ill patients with COVID-19.

Interferon gamma-induced protein 10 (IP-10) for the early prognosis of the risk for severe respiratory failure and death in COVID-19 pneumonia.

OBJECTIVES: Elevated concentrations of soluble urokinase plasminogen activator receptor (suPAR) predict progression to severe respiratory failure (SRF) or death among patients with COVID-19 pneumonia and guide early anakinra treatment. As suPAR testing may not be routinely available in every health-care setting, alternative biomarkers are needed. We investigated the performance of C-reactive protein (CRP), interferon gamma-induced protein-10 (IP-10) and TNF-related apoptosis-inducing ligand (TRAIL) for predicting SRF or death in COVID-19. METHODS: Two cohorts were studied; one discovery cohort with 534 patients from the SAVE-MORE clinical trial; and one validation cohort with 364 patients from the SAVE trial including also 145 comparators. CRP, IP-10 and TRAIL were measured by the MeMed Key® platform in order to select the biomarker with the best prognostic performance for the early prediction of progression into SRF or death. RESULTS: IP-10 had the best prognostic performance: baseline concentrations 2000 pg/ml or higher predicted equally well to suPAR (sensitivity 85.0 %; negative predictive value 96.6 %). Odds ratio for poor outcome among anakinra-treated participants of the SAVE-MORE trial was 0.35 compared to placebo when IP-10 was 2,000 pg/ml or more. IP-10 could divide different strata of severity for SRF/death by day 14 in the validation cohort. Anakinra treatment decreased this risk irrespective the IP-10 concentrations. CONCLUSIONS: IP-10 concentrations of 2,000 pg/ml or higher are a valid alternative to suPAR for the early prediction of progression into SRF or death the first 14 days from hospital admission for COVID-19 and they may guide anakinra treatment. CLINICALTRIALS: gov, NCT04680949 and NCT04357366.

Ribavirin aerosol in hospitalized adults with respiratory distress and COVID-19: An open-label trial.

There is an unmet medical need for effective treatments for hospitalized patients with coronavirus disease 2019 (COVID-19). Ribavirin is a broad-spectrum antiviral with demonstrated in vitro activity against multiple viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This trial evaluated the potential of ribavirin inhalation solution (ribavirin aerosol) to reduce COVID-19 disease severity in adults with confirmed SARS-CoV-2 infection and a diagnosis of respiratory distress. This phase I, multicenter, open-label, nonrandomized trial was conducted from February 2021 through August 2021. Patients received ribavirin aerosol (100 mg/ml for 30 min or 50 mg/ml for 60 min) twice daily for up to 6 days. The primary end point was change from baseline in clinical status severity, rated on a 7-point scale (1 [death]; 7 [not hospitalized; no limitations on activities]), at day 7 (or end-of-treatment/early termination) and day 30 (follow-up). Fifty-one patients were treated with ribavirin aerosol (mean age, 51.5 years; 78.4% men); mean number of doses was 9.7 (range, 1-12). Improvement of ≥1 level in clinical status severity was observed in 31.4% (16/51) and 78.4% (40/51) of patients at end-of-treatment and day 30, respectively. Of 21 patients who required a ventilator, 16 (76.2%) were able to discontinue ventilator use. Five patients (9.8%) died between end-of-treatment and day 30. Three patients (5.9%) discontinued study treatment due to adverse events. No deaths were considered related to study treatment. These data provide preliminary evidence that ribavirin aerosol may be an efficacious treatment for respiratory distress in adults with COVID-19.

A randomized clinical trial of lipid metabolism modulation with fenofibrate for acute coronavirus disease 2019.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cytotoxicity may involve inhibition of peroxisome proliferator-activated receptor alpha. Fenofibrate activates peroxisome proliferator-activated receptor alpha and inhibits SARS-CoV-2 replication in vitro. Whether fenofibrate can be used to treat coronavirus disease 2019 (COVID-19) infection in humans remains unknown. Here, we randomly assigned inpatients and outpatients with COVID-19 within 14 d of symptom onset to 145 mg of oral fenofibrate nanocrystal formulation versus placebo for 10 d, in a double-blinded fashion. The primary endpoint was a severity score whereby participants were ranked across hierarchical tiers incorporating time to death, mechanical ventilation duration, oxygenation, hospitalization and symptom severity and duration. In total, 701 participants were randomized to fenofibrate (n = 351) or placebo (n = 350). The mean age of participants was 49 ± 16 years, 330 (47%) were female, mean body mass index was 28 ± 6 kg/m2 and 102 (15%) had diabetes. Death occurred in 41 participants. Compared with placebo, fenofibrate had no effect on the primary endpoint. The median (interquartile range) rank in the placebo arm was 347 (172, 453) versus 345 (175, 453) in the fenofibrate arm (P = 0.819). There was no difference in secondary and exploratory endpoints, including all-cause death, across arms. There were 61 (17%) adverse events in the placebo arm compared with 46 (13%) in the fenofibrate arm, with slightly higher incidence of gastrointestinal side effects in the fenofibrate group. Overall, among patients with COVID-19, fenofibrate has no significant effect on various clinically relevant outcomes ( NCT04517396 ).

Greek Remdesivir Cohort (GREC) Study: Effectiveness of Antiviral Drug Remdesivir in Hospitalized Patients with COVID-19 Pneumonia.

In several randomized studies, remdesivir (RDV) has been reported to shorten the recovery period and improve clinical outcomes in COVID-19 patients, and thus, it is recommended as a standard of care. Nevertheless, controversial reports have been published. The aim of the present study is to evaluate the effectiveness of remdesivir in hospitalized patients with COVID-19 pneumonia at three Greek University Departments of Infectious Diseases with homogenous treatment protocols. From September 2020 to February 2021, we retrospectively analyzed adults hospitalized with confirmed SARS-CoV-2 infection and radiological findings of pneumonia, who received remdesivir once daily for five days. Exploratory end points were duration of hospitalization, time of intubation, and death. Overall, 551 patients were included in the study. The optimal cutoff point for the number of days needed after symptom initiation for drug administration associated with better clinical outcome was 7 days. Higher odds for discharge and lower for intubation were observed in patients with treatment initiation ≤7 days (p = 0.052 and p = 0.019, retrospectively) regardless of gender (p = 0.537), hypertension (p = 0.096), dyslipidemia (p = 0.221), diabetes mellitus (p = 0.306), and usage of immunomodulators (p = 0.408). Our study has demonstrated beneficial effects of early treatment with remdesivir (≤7 days from symptom onset) on rates of intubation and probability of discharge.

New Insights into SARS-CoV-2 and Cancer Cross-Talk: Does a Novel Oncogenesis Driver Emerge?

Since the pandemic's onset, a growing population of individuals has recovered from SARS-CoV-2 infection and its long-term effects in some of the convalescents are gradually being reported. Although the precise etiopathogenesis of post-acute COVID-19 sequelae (PACS) remains elusive, the mainly accepted rationale is that SARS-CoV-2 exerts long-lasting immunomodulatory effects, promotes chronic low-grade inflammation, and causes irreversible tissue damage. So far, several viruses have been causally linked to human oncogenesis, whereas chronic inflammation and immune escape are thought to be the leading oncogenic mechanisms. Excessive cytokine release, impaired T-cell responses, aberrant activation of regulatory signaling pathways (e.g., JAK-STAT, MAPK, NF-kB), and tissue damage, hallmarks of COVID-19 disease course, are also present in the tumor microenvironment. Therefore, the intersection of COVID-19 and cancer is partially recognized and the long-term effects of the virus on oncogenesis and cancer progression have not been explored yet. Herein, we present an up-to-date review of the current literature regarding COVID-19 and cancer cross-talk, as well as the oncogenic pathways stimulated by SARS-CoV-2.

Programmed Cell Death Protein 1 Axis Inhibition in Viral Infections: Clinical Data and Therapeutic Opportunities.

A vital function of the immune system is the modulation of an evolving immune response. It is responsible for guarding against a wide variety of pathogens as well as the establishment of memory responses to some future hostile encounters. Simultaneously, it maintains self-tolerance and minimizes collateral tissue damage at sites of inflammation. In recent years, the regulation of T-cell responses to foreign or self-protein antigens and maintenance of balance between T-cell subsets have been linked to a distinct class of cell surface and extracellular components, the immune checkpoint molecules. The fact that both cancer and viral infections exploit similar, if not the same, immune checkpoint molecules to escape the host immune response highlights the need to study the impact of immune checkpoint blockade on viral infections. More importantly, the process through which immune checkpoint blockade completely changed the way we approach cancer could be the key to decipher the potential role of immunotherapy in the therapeutic algorithm of viral infections. This review focuses on the effect of programmed cell death protein 1/programmed death-ligand 1 blockade on the outcome of viral infections in cancer patients as well as the potential benefit from the incorporation of immune checkpoint inhibitors (ICIs) in treatment of viral infections.

Insights into CD24 and Exosome Physiology and Potential Role in View of Recent Advances in COVID-19 Therapeutics: A Narrative Review.

Cluster of differentiation (CD) 24, a long-known protein with multifaceted functions, has gained attention as a possible treatment for Coronavirus Disease 19 (COVID-19) due to its known anti-inflammatory action. Extracellular vesicles (EVs), such as exosomes and microvesicles, may serve as candidate drug delivery platforms for novel therapeutic approaches in COVID-19 and various other diseases due to their unique characteristics. In the current review, we describe the physiology of CD24 and EVs and try to elucidate their role, both independently and as a combination, in COVID-19 therapeutics. CD24 may act as an important immune regulator in diseases with complex physiologies characterized by excessive inflammation. Very recent data outline a possible therapeutic role not only in COVID-19 but also in other similar disease states, e.g., acute respiratory distress syndrome (ARDS) and sepsis where immune dysregulation plays a key pathophysiologic role. On the other hand, CD24, as well as other therapeutic molecules, can be administered with the use of exosomes, exploiting their unique characteristics to create a novel drug delivery platform as outlined in recent clinical efforts. The implications for human therapeutics in general are huge with regard to pharmacodynamics, pharmacokinetics, safety, and efficacy that will be further elucidated in future randomized controlled trials (RCTs).

Corrigendum: ACTIVATE-2: A double-blind randomized trial of BCG vaccination against COVID-19 in individuals at risk.

[This corrects the article DOI: 10.3389/fimmu.2022.873067.].

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.

A Randomized Trial of Lipid Metabolism Modulation with Fenofibrate for Acute Coronavirus Disease 2019.

Background Abnormal cellular lipid metabolism appears to underlie SARS-CoV-2 cytotoxicity and may involve inhibition of peroxisome proliferator activated receptor alpha (PPARα). Fenofibrate, a PPAR-α activator, modulates cellular lipid metabolism. Fenofibric acid has also been shown to affect the dimerization of angiotensin-converting enzyme 2, the cellular receptor for SARS-CoV-2. Fenofibrate and fenofibric acid have been shown to inhibit SARS-CoV-2 replication in cell culture systems in vitro . Methods We randomly assigned 701 participants with COVID-19 within 14 days of symptom onset to 145 mg of fenofibrate (nanocrystal formulation with dose adjustment for renal function or dose-equivalent preparations of micronized fenofibrate or fenofibric acid) vs. placebo for 10 days, in a double-blinded fashion. The primary endpoint was a ranked severity score in which participants were ranked across hierarchical tiers incorporating time to death, duration of mechanical ventilation, oxygenation parameters, subsequent hospitalizations and symptom severity and duration. ClinicalTrials.gov registration: NCT04517396. Findings: Mean age of participants was 49 ± 16 years, 330 (47%) were female, mean BMI was 28 ± 6 kg/m 2 , and 102 (15%) had diabetes mellitus. A total of 41 deaths occurred. Compared with placebo, fenofibrate administration had no effect on the primary endpoint. The median (interquartile range [IQR]) rank in the placebo arm was 347 (172, 453) vs. 345 (175, 453) in the fenofibrate arm (P = 0.819). There was no difference in various secondary and exploratory endpoints, including all-cause death, across randomization arms. These results were highly consistent across pre-specified sensitivity and subgroup analyses. Conclusion Among patients with COVID-19, fenofibrate has no significant effect on various clinically relevant outcomes.