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BackgroundBaricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.MethodsIn this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168.FindingsBetween Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012).InterpretationIn hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered.FundingNational Institute of Allergy and Infectious Diseases.

Background Remdesivir (RDV) has been a mainstay of COVID-19 therapy for hospitalized patients. Impact of RDV timing in relationship to symptom-onset in hospitalized patients remains unclear, though early treatment is theorized to improve antiviral activity and clinical outcomes. Methods This was a single-center retrospective study of adult patients hospitalized for severe COVID-19 treated with RDV. Patient charts were reviewed by 2 independent investigators to determine disease course and outcomes. Patients were stratified based on time from symptom-onset to RDV (short: ≤7 vs. long: >7 days). The primary outcome was time to clinical recovery within 28 days. Secondary outcomes were proportion of patients recovered and proportion discharged from the hospital within 10, 14, and 28 days; and mortality within 28 days. Time to recovery was analyzed using the Kaplan-Meier method and the significance was tested by log rank tests. Cox’s proportional hazards models were used to estimate hazard ratios (HR). Fisher’s exact test was used to compare recovery rates between groups. Results Overall, 405 patient charts were reviewed, and 337 met the inclusion criteria. On the first day of RDV, 178 (53%) of patients had symptoms for 7 days. Patients in the short symptom duration group were slightly older (66.5 vs. 59 years, p=0.004) and had more co-morbidities. Median time to recovery was 7 (95% CI 5-9) in the short- vs. 5 (95% CI 4-6) days in the long-symptom duration groups, respectively, p=0.066. By day 10, 111 (62%) vs. 116 (73%) patients met the clinical recovery definition (p=0.048), and 113 (63%) vs. 119 (75%) patients were discharged from the hospital (p=0.026) in the short- vs. long-symptom duration groups, respectively. In the Cox’s proportional hazards model, age, disease severity, and co-morbidities (kidney, liver, chronic respiratory diseases, and type II diabetes mellitus) were associated with longer recovery times. Conclusion In this cohort, long duration of symptoms ( >7 days) prior to initiation of RDV therapy was not associated with longer recovery time or longer hospitalization. Additional studies are needed to elucidate benefits of RDV therapy in relationship to the time course of severe COVID-19 in hospitalized patients. Disclosures Ramy H. Elshaboury, PharmD, Eli Lilly: Honoraria|Gilead Sciences: Grant/Research Support Fiona Cheung, PharmD, Pfizer Inc.: Employee Bryan Polsonetti, PharmD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Essy Mozaffari, PharmD, MPH, MBA, Gilead: Employee|Gilead: Stocks/Bonds Linda Chen, MPH, Gilead Sciences: Employee|Gilead Sciences: Stocks/Bonds|UCB pharmaceuticals: Stocks/Bonds Elizabeth Hohmann, MD, Gilead: Advisor/Consultant|Kowa Pharmaceuticals: Advisor/Consultant|Tend, Inc: Grant/Research Support.

To evaluate whether the use of inhaled nitric oxide (iNO)200 improves respiratory function.This retrospective cohort study used data from pregnant patients hospitalized with severe bilateral coronavirus disease 2019 (COVID-19) pneumonia at four teaching hospitals between March 2020 and December 2021. Two cohorts were identified: 1) those receiving standard of care alone (SoC cohort) and 2) those receiving iNO200 for 30 minutes twice daily in addition to standard of care alone (iNO200 cohort). Inhaled nitric oxide, as a novel therapy, was offered only at one hospital. The prespecified primary outcome was days free from any oxygen supplementation at 28 days postadmission. Secondary outcomes were hospital length of stay, rate of intubation, and intensive care unit (ICU) length of stay. The multivariable-adjusted regression analyses accounted for age, body mass index, gestational age, use of steroids, remdesivir, and the study center.Seventy-one pregnant patients were hospitalized for severe bilateral COVID-19 pneumonia: 51 in the SoC cohort and 20 in the iNO200 cohort. Patients receiving iNO200 had more oxygen supplementation-free days (iNO200: median [interquartile range], 24 [23-26] days vs standard of care alone: 22 [14-24] days, P=.01) compared with patients in the SoC cohort. In the multivariable-adjusted analyses, iNO200 was associated with 63.2% (95% CI 36.2-95.4%; P.001) more days free from oxygen supplementation, 59.7% (95% CI 56.0-63.2%; P.001) shorter ICU length of stay, and 63.6% (95% CI 55.1-70.8%; P.001) shorter hospital length of stay. No iNO200-related adverse events were reported.In pregnant patients with severe bilateral COVID-19 pneumonia, iNO200 was associated with a reduced need for oxygen supplementation and shorter hospital stay.

ImportanceRecurrent Clostridioides difficile infection (CDI) is a debilitating disease leading to poor health-related quality of life (HRQOL), loss of productivity, anxiety, and depression. The potential association of treatment with HRQOL has not been well evaluated.ObjectivesTo explore the association of SER-109 compared with placebo on HRQOL in patients with recurrent CDI up to week 8.Design, Setting, and ParticipantsThis study was a secondary analysis of a randomized, double-blind, placebo-controlled trial that took place at 56 sites in the US and Canada from July 2017 to April 2020 and included 182 patients randomized to SER-109 or placebo groups.InterventionsSER-109 or placebo (4 capsules once daily for 3 days) following antibiotics for CDI.Main Outcomes and MeasuresExploratory analysis of HRQOL using the disease specific Clostridioides difficile Quality of Life Survey (Cdiff32) assessed at baseline, week 1, and week 8.ResultsIn this study, 182 patients (109 [59.9%] female; mean age, 65.5 [16.5] years) were randomized to SER-109 (89 [48.9%]) or placebo (93 [51.1%]) groups and were included in the primary and exploratory analyses. Baseline Cdiff32 scores were similar between patients in the SER-109 and placebo groups (52.0 [18.3] vs 52.8 [18.7], respectively). The proportion of patients with overall improvement from baseline in the Cdiff32 total score was higher in the SER-109 arm than placebo at week 1 (49.4% vs 26.9%; P = .012) and week 8 (66.3% vs 48.4%; P = .001).Greater improvements in total and physical domain and subdomain scores were observed in patients in the SER-109 group compared with placebo as early as week 1, with continued improvements observed at week 8. Among patients in the placebo group, improvements in HRQOL were primarily observed in patients with nonrecurrent CDI while patients in the SER-109 group reported improvements in HRQOL, regardless of clinical outcome.Conclusions and RelevanceIn this secondary analysis of a phase 3 clinical trial, SER-109, an investigational microbiome therapeutic was associated with rapid and steady improvement in HRQOL compared with placebo through 8 weeks, an important patient-reported outcome.Trial RegistrationClinicalTrials.gov Identifier: NCT03183128

Summary Background Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19. Methods We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov , NCT04492475 . Findings Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87–1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3–7%) in the interferon beta-1a plus remdesivir group and 3% (2–6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69–2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group. Interpretation Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo. Funding The National Institute of Allergy and Infectious Diseases (USA).

OBJECTIVES:. We sought to validate prognostic scores in coronavirus disease 2019 including National Early Warning Score, Modified Early Warning Score, and age-based modifications, and define their performance characteristics. DESIGN:. We analyzed prospectively collected data from the Adaptive COVID-19 Treatment Trial. National Early Warning Score was collected daily during the trial, Modified Early Warning Score was calculated, and age applied to both scores. We assessed prognostic value for the end points of recovery, mechanical ventilation, and death for score at enrollment, average, and slope of score over the first 48 hours. SETTING:. A multisite international inpatient trial. PATIENTS:. A total of 1,062 adult nonpregnant inpatients with severe coronavirus disease 2019 pneumonia. INTERVENTIONS:. Adaptive COVID-19 Treatment Trial 1 randomized participants to receive remdesivir or placebo. The prognostic value of predictive scores was evaluated in both groups separately to assess for differential performance in the setting of remdesivir treatment. MEASUREMENTS AND MAIN RESULTS:. For mortality, baseline National Early Warning Score and Modified Early Warning Score were weakly to moderately prognostic (c-index, 0.60–0.68), and improved with addition of age (c-index, 0.66–0.74). For recovery, baseline National Early Warning Score and Modified Early Warning Score demonstrated somewhat better prognostic ability (c-index, 0.65–0.69); however, National Early Warning Score+age and Modified Early Warning Score+age further improved performance (c-index, 0.68–0.71). For deterioration, baseline National Early Warning Score and Modified Early Warning Score were weakly to moderately prognostic (c-index, 0.59–0.69) and improved with addition of age (c-index, 0.63–0.70). All prognostic performance improvements due to addition of age were significant (p < 0.05). CONCLUSIONS:. In the Adaptive COVID-19 Treatment Trial 1 cohort, National Early Warning Score and Modified Early Warning Score demonstrated moderate prognostic performance in patients with severe coronavirus disease 2019, with improvement in predictive ability for National Early Warning Score+age and Modified Early Warning Score+age. Area under receiver operating curve for National Early Warning Score and Modified Early Warning Score improved in patients receiving remdesivir versus placebo early in the pandemic for recovery and mortality. Although these scores are simple and readily obtainable in myriad settings, in our data set, they were insufficiently predictive to completely replace clinical judgment in coronavirus disease 2019 and may serve best as an adjunct to triage, disposition, and resourcing decisions.

Background In South Asia, data on enteric fever are sparse outside of urban areas. We characterized enteric fever diagnosis patterns and the burden of culture-confirmed cases in peri-urban and rural Nepal. Methods We used national reports to estimate enteric fever diagnosis rates over 20 years (1994–2014) and conducted a prospective study of patients presenting with a >72-hour history of fever to 4 peri-urban and rural healthcare facilities (during August 2013–June 2016). We compared clinical characteristics of patients with culture-confirmed Salmonella Typhi or Paratyphi infection to those of patients without enteric fever. We used generalized additive models with logistic link functions to evaluate associations of age and population density with culture positivity. Results National rates of enteric fever diagnosis were high, reaching 18.8 cases per 1000 during 2009–2014. We enrolled 4309 participants with acute febrile illness. Among those with a provisional clinical diagnosis, 55% (1334 of 2412) received a diagnosis of enteric fever; however, only 4.1% of these had culture-confirmed typhoidal Salmonella infection. Culture positivity was highest among young adults and was strongly associated with higher population density (P < .001). Conclusions Enteric fever diagnosis rates were very high throughout Nepal, but in rural settings, few patients had culture-confirmed disease. Expanded surveillance may inform local enteric fever treatment and prevention strategies.

Background Following standard of care antibiotics, investigational microbiome therapeutic, SER-109, achieved superiority vs placebo (PBO) at 8 weeks in reducing rCDI in patients with ≥3 prior episodes (12.4% vs 39.8%, respectively; p< 0.001). We evaluated the impact of SER-109 vs PBO on HRQoL with general (EQ-5D-5L) and disease-specific (Cdiff32) measures [Garey 2016]. Methods EQ-5D-5L measures outcomes in 5 domains (mobility, self-care, activities, pain/discomfort, and anxiety/depression) while Cdiff32 measures outcomes in 3 domains (physical, mental, and social) including 5 associated subdomains. Patients completed EQ-5D-5L and Cdiff32 measures at baseline (BL), Wk 8, and at recurrence/early termination. Changes from BL were assessed between SER-109 vs PBO and by clinical outcome (recurrence versus nonrecurrence) in the ITT population and within each treatment arm. The between treatment group comparison analysis controlled for age, gender, prior antibiotics, and number of prior CDI episodes. Results Mean EQ-5D-5L and Cdiff32 scores were comparable between SER-109 and PBO at BL. EQ-5D-5L did not detect differences at Wk 8 from BL between SER-109 and PBO or by clinical outcome. In contrast, Cdiff32 detected significant improvements at Wk 8 from BL within both SER-109 subjects and PBO subjects (Fig1) and by recurrence status (Fig2). Subjects achieved significant improvement in all domains at Wk 8 from BL regardless of treatment group. When examining recurrence status within treatment arms, all PBO subjects with non-recurrence showed improvement in all health domains, while PBO subjects with recurrence had declines in several subdomains (Fig3B). Similarly, SER-109 subjects with non-recurrence showed improvement in all domains compared to BL. However, overall and mental domain/subdomains scores also improved in SER-109 subjects with recurrence (Fig3A). Conclusion Significant HRQoL improvements were associated with CDI nonrecurrence, which highlights the negative impact of this debilitating infection. SER-109 was associated with improved overall and mental scores, regardless of clinical outcome. Further investigation is warranted on the impact of SER-109 on mental health even among those with CDI recurrence. Disclosures Elizabeth Hohmann, MD, Seres Therapeutics (Research Grant or Support) Paul Feuerstadt, MD, FACG, Ferring/Rebiotix Pharmaceuticals (Consultant, Scientific Research Study Investigator, Speaker’s Bureau)Finch Pharmaceuticals (Scientific Research Study Investigator)Merck and Co (Speaker’s Bureau)SERES Therapeutics (Consultant, Scientific Research Study Investigator)Takeda Pharmaceuticals (Consultant) Christine Lee, MD, FRCPC, Pfizer (Board Member)Rebiotix-Ferring (Board Member)Rebiotix-Ferring (Grant/Research Support)Seres (Grant/Research Support)Summit (Grant/Research Support) Sissi Pham, PharmD, Seres (Consultant) Pat Ray Reese, PhD, Reese Associates, LLC (Consultant, Independent Contractor) Elaine E. Wang, MD, Seres Therapeutics (Employee) Elaine E. Wang, MD, Seres Therapeutics (Employee, Shareholder) Lisa von Moltke, MD, Seres Therapeutics (Employee, Shareholder) Kevin W. Garey, Pharm.D., M.S., FASHP, Summit Therapeutics (Research Grant or Support)