bluuebunny/crossref_metadata_2025_split huggingface dataset:
517. Subcutaneous Sarilumab for the Treatment of Hospitalized patients with Moderate to Severe COVID19 Disease: A Pragmatic, Embedded, Multi-Center Randomized Clinical Trial
Authors: Branch-Elliman Westyn , Ferguson Ryan , Doros Gheorghe , Woods Patricia , Leatherman Sarah , Strymish Judith , Datta Rupak , Goswami Rekha , Jankowich Matthew , Shah Nishant , Taylor Thomas H , Page Sarah T , Schiller Sara , Shannon Colleen , Hau Cynthia , Flynn Maura , Holmberg Erika , Visnaw Karen , Dhond Rupali , Brophy Mary , Monach Paul 
Published: December 2021

Abstract

Background
The aim of this pragmatic, embedded adaptive trial was to measure the effectiveness of subcutaneous sarilumab in addition to an evolving standard of care for clinical management of inpatients with moderate to severe COVID-19 disease (NCT04359901). The study is also a real-world demonstration of the realization of a prospective learning healthcare system.

Methods
Two-arm, randomized, open-label controlled 5-center trial comparing standard care alone to standard care (SOC), which evolved over time, with addition of subcutaneous sarilumab (200 mg or 400 mg anti-IL6R) among hospitalized patients with moderate to severe COVID-19 not requiring mechanical ventilation. The primary outcome was 14-day incidence of intubation or death. The trial used a randomized play-the-winner design and was fully embedded within the EHR system, including the adaptive randomization process.

Results
Among 417 patients screened, 162 were eligible based on chart review, 53 consented, and 50 were evaluated for the primary endpoint of intubation or death ( &gt;30% of eligible patients enrolled) (Figure 1). After the second interim review, the unblinded Data Monitoring Committee recommended that the study be stopped due to concern for safety: a high probability that rates of intubation or death were higher with addition of sarilumab to SOC (92.6%), and a very low probability (3.4%) that sarilumab would be found to be superior.
Figure 1. Key Study Milestones, Outcomes, and Adaptations

Conclusion
This randomized trial of patients hospitalized with COVID-19 and requiring supplemental oxygen but not mechanical ventilation found no evidence of benefit from subcutaneous sarilumab in addition to an evolving standard-of-care. The numbers of patients and events were too low to allow independent conclusions to be drawn, but this study contributes valuable information about the role of subcutaneous IL-6 inhibition in the treatment of patients hospitalized with COVID-19. The major innovation of this trial was the advancement of embedded, point-of-care clinical trials for FDA-approved drugs; this represents a realization of the learning healthcare system. Methods developed and piloted during the conduct of this trial can be used in future investigations to speed the advancement of clinical science.

Disclosures
Nishant Shah, MD, General Electric (Shareholder)Pfizer, Inc. (Research Grant or Support) Karen Visnaw, RN, Liquidia (Shareholder) Paul Monach, MD,PhD, Celgene (Consultant)ChemoCentryx (Consultant)Kiniksa (Advisor or Review Panel member)
519. Risk Factor Analysis for Hospital Admission Following Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Monoclonal Antibody Treatment
Authors: Abusalem Lana , Wood Cole , Crescencio Juan Carlos Rico , Dare Ryan K 
Published: December 2021

Abstract

Background
The FDA has issued emergency use authorization (EUA) for neutralizing monoclonal antibodies (mAb) for the treatment of mild-moderate coronavirus disease 2019 (COVID-19) in patients who are at high risk of disease progression. The EUA allows for COVID-19 mAb infusion to occur up to 10 days from symptom onset and due to logistics, mAb treatment typically occurs later in this 10 day window. Efficacy of early versus late mAb treatment is unknown

Methods
In this single center, retrospective case-control study, we performed a risk factor analysis of patients with mild COVID-19 infection treated with mAb on the composite outcome of subsequent evaluation in the Emergency Department (ED) or inpatient admission December 2020 through May 2021. Multivariate analysis of variables found to be significant in univariate analysis was performed using STATA 15 statistical software

Results
Two-hundred eighty-eight patients who received mAb treatment were included in analysis. The mean age was 58.6 years and 59.7% were female, 64.9% white, and 27.1% African American. Following mAb infusion, 31 (10.8%) had disease progression resulting in an ED encounter or inpatient admission. Patients who received early (days 1-5 of symptoms) mAb infusion were less likely to have progressive disease than patients with late (days 6-12 of symptoms) infusion; (6.1% vs 13.2%; P= 0.048). Zero of 21 patients who received mAb infusion on day 1-3 of symptoms had disease progression. Patients with CHF (7.4% vs 19.4%; P=0.038), cirrhosis (9.3% vs 25.8%; p=0.012), CKD (12.5% vs 35.5%; p=0.001) and hypertension (70.8% vs 90.3%; p=0.021) were more likely to have disease progression. There were no differences in sex, race, BMI, or symptoms between groups. Multivariate analysis revealed cirrhosis (OR 3.0; 95% CI 1.1-7.9) and CKD (OR 2.6; 95% CI 1.0-6.4) increased risk of disease progression while early mAb infusion was protective (OR 0.38; 95% CI 0.14-1.0)

Conclusion
Infusion of mAb for the treatment of mild to moderate Covid-19 within 5 days of symptom onset reduces rate of disease progression compared to delayed (day 6-12 of symptoms) infusion. This finding was significant when controlling for comorbidities. Efforts should be made to infuse high risk patients with COVID-19 mAb therapy within 5 days of symptom onset

Disclosures
All Authors: No reported disclosures
523. Use of Immune-Viral Dynamics Modeling to Understand Molnupiravir Drug Effect for COVID-19
Authors: Cao Youfang , Gao Wei , Birger Ruthie , Stone Julie 
Published: December 2021

Abstract

Background
Molnupiravir (MOV) is an orally administered ribonucleoside prodrug of β-D-N4-hydroxycytidine (NHC) against SARS-CoV-2. Here we present viral dynamics analysis of Phase 2 clinical virology data to inform MOV Phase 3 study design and development strategy.

Methods
An Immune-Viral Dynamics Model (IVDM) was developed with mechanisms of SARS-CoV-2 infection, replication, and induced immunity, which together describe the dynamics of viral load (VL) during disease progression. Longitudinal virology data from ferret studies (Cox, et al. Nat. Microbiol 2021:6-11) were used to inform IVDM, which was further translated to human by adjusting parameter values to capture clinical data from MOVe-IN/MOVe-OUT studies. Different placements of drug effects (on viral infectivity vs. productivity) and representations of immune response were explored to identify the best ones to describe data. A simplified 95% drug effect was implemented to represent a highly effective dose of MOV.

Results
IVDM showed data were best described when MOV acts on viral infectivity, consistent with the error catastrophe mechanism of action. A cascade of innate and adaptive immune response and a basal level activation enabled durable immunity and continued viral decay after treatment end. IVDM reasonably describes VL and viral titer data from animals and humans. Influence of MOV start time was explored using simulations. Consistent with the ferret studies, simulations showed when treatment is started within the first week post infection, MOV reduces viral growth, resulting in a lower and shortened duration of detectable VL. When started later (e.g. &gt;7 days since symptom onset), the magnitude of drug effect is substantially diminished in a typical patient with an effective immune response which reduces VL prior to treatment start. Further work is needed to model response in patients with longer term infection, where MOV drug effects may have more persistent utility.

Conclusion
A COVID-19 IVDM developed using multiscale MOV virology data supports drug action on viral infectivity and importance of interplay of treatment and immune response and can describe infection time course and drug effect. IVDM provided mechanistic interpretations for VL drug effect in clinical studies.

Disclosures
Youfang Cao, PhD, Merck & Co. (Employee) Wei Gao, PhD, Merck & Co., Inc. (Employee, Shareholder) Ruthie Birger, PhD, Merck (Employee) Julie Stone, PhD, Merck & Co., Inc. (Employee, Shareholder)
524. Assessing the Safety of an Outpatient Remdesivir Infusion Program for Patients with Severe COVID-19 in the Setting of a Pandemic Surge
Authors: Gee Benjamin , Cheruvanky Anita , Faiad Graciela , Li Aldon , Pham Huan , Quijada Earl , Sun Susan , Baghban Adam 
Published: December 2021

Abstract

Background
(i) Remdesivir (RDV) shortens recovery time among COVID-19 patients in an inpatient setting. (ii) Treatments for outpatients diagnosed with COVID-19 are limited. (iii) In early 2021, there was a national surge in COVID-19 hospitalizations, which resulted in hospital bed and staff shortages. (iv) In the face of this pandemic surge, we piloted a program to expand our RDV treatment capacity by establishing an off-label, outpatient infusion tent (OIT) for patients with severe COVID-19. (v) This is a retrospective, descriptive report examining the safety and efficacy of this program, with outcomes of interest being 30-day mortality and hospital admission within the subsequent 30 days

Methods
(i) The OIT, consisting of 11 chairs capable of treating 35 patients per day, was operational from January 1 to February 19, 2021. (ii) Patients were referred to the outpatient RDV program primarily from urgent care (UC) and the emergency department (ED), and from the inpatient setting to complete therapy. Patients received at least one dose prior to referral. (iii) Eligibility criteria included a confirmed COVID-19 diagnosis, radiographic evidence of viral pneumonia, and an oxygen saturation less than or equal to 94 on room air. (iv) Exclusion criteria included pregnancy, sepsis, end-stage renal disease or GFR &lt; 30, hepatitis with transaminases 10 times the limit of normal. Patients with BMI &gt; 40, age &gt; 75, chronic lung disease, dementia, were considered on a case by case basis. (v) Patients received dexamethasone and deep vein thrombosis prophylaxis

Results
(i) A total of 88 patients received 258 infusions. The average number of outpatient infusions per participant was 2.9. (ii) Four out of 88 patients died (4.5%) within 30 days of first dose in the infusion tent. No deaths occurred in the outpatient setting. (iii) Fourteen out of 88 patients were admitted to the hospital within the subsequent 30 days (15.9%). (iv) 11/14 admissions (78.6%) were due to progression of COVID-19. There were no admissions due to adverse drug reactions
Table 1. Patient Characteristics

Table 2. Admissions Within Subsequent 30 Days

Conclusion
Mortality rate in outpatients with severe COVID-19 treated with RDV was similar to that reported in inpatients. In this cohort of patients with severe COVID, a majority (84.1%) avoided hospitalization while still receiving appropriate treatment. Results suggest RDV can be safely delivered to outpatients with severe COVID-19.

Disclosures
All Authors: No reported disclosures
526. Implementation of Use of Monoclonal Antibody Therapy in a Large Academic Center for the Outpatient Treatment of Covid-19: Impact on 30 Day Hospitalization Rates, ED Visits and Death
Authors: Bhimani Azra , Srinivasan Vinay , Weinstein Stacey , Clemons Nathan , Batiste Quanna , Yang Shangxin , Garner Omai , Vijayan Tara 
Published: December 2021

Abstract

Background
Monoclonal Antibody Therapy (MAbs) has been shown to reduce rates of ED visits and hospitalizations in patients at risk for severe Covid-19 infection in clinical trials. Since November, three Mabs received emergency use authorization: Bamlanivimab (Bam), Bamlanivimab/Etesevimab (Bam/Ete) and Casirivimab/Imdevimab (Casi/imdevi). We describe here the real-world effectiveness of implementing early MAb therapy in the outpatient setting for individuals with Covid-19 at high risk of progression.

Methods
We examined the records of 808 UCLA Health patients with a confirmed positive SARS-CoV2 PCR test who were either referred for outpatient Mab therapy or received Mab treatment in the emergency department (ED) between December 10, 2020, and May 3, 2021. The primary outcome of our analysis was the combined 30-day incidence of emergency department visits, hospitalizations, or death following the date of referral. SARS-CoV2 isolates of hospitalized patients who had received Mabs were sequenced to determine the presence of variants.

Results
Of 808 patients, 383 were referred for treatment but did not receive treatment, 109 received Mabs in the ED and 316 patients were treated in an outpatient setting. Composite 30-day mortality, ED visits and hospital admissions were significantly reduced in the combination therapy group (Bam/Ete or Cas/Imd) compared with monotherapy (Bam alone) or no treatment groups (aHR 0.16, 95% CI .038, .67). Significant factors associated with the composite outcome included: history of lung disease (HR 4.46, 95% CI 2.89-6.90), cardiovascular disease (HR 1.87, 95% CI 1.12-3.12), kidney disease (HR 2.04, 95% CI 1.27-3.25), and immunocompromised state (HR 3.24, 95% CI 1.02-10.26) as well as high social vulnerability index (HR 1.87, 95% CI 1.13-3.10). Over one-third of hospitalized patients who had received Mabs were confirmed to have the California variant (B.1.427/29) (Figure 1).

Figure 1. Covid-19 MAB Treatment Failure Lineages

Conclusion
Our data show that in a real-world setting, combination monoclonal antibody therapy, not monotherapy, significantly reduced ED visits and hospital admissions, likely due to the presence of the California variants. High socioeconomic vulnerability and certain medical conditions increased risk of treatment failure.

Disclosures
Omai Garner, PhD, D(ABMM), Beckman Coulter (Scientific Research Study Investigator)
527. Lower Risk of ICU Admission with Remdesivir in Patients Hospitalized with COVID-19 Pneumonia
Authors: Lim Sarah , Schreiner Pamela , Lifson Alan , Bye Erica , Como-Sabetti Kathryn , Lynfield Ruth , Lynfield Ruth 
Published: December 2021

Abstract

Background
Remdesivir (RDV) was approved by FDA in October 2020 for use in hospitalized patients with COVID-19. We examined the association between RDV treatment and ICU admission in patients hospitalized with COVID-19 pneumonia requiring supplemental oxygen (but not advanced respiratory support) in MN.

Methods
COVID-19-Associated Hospitalization Surveillance Network (COVID-NET) is population-based surveillance of hospitalized laboratory confirmed cases of COVID-19. We analyzed COVID-NET cases ≥18 years hospitalized between Mar 23, 2020 and Jan 23, 2021 in MN for which medical record reviews were complete. On admission, included cases had evidence of COVID-19 pneumonia on chest imaging with oxygen saturation &lt; 94% on room air or requiring supplemental oxygen. Cases were excluded if treated with RDV after ICU admission. Multivariable logistic regression was performed to assess the association between RDV treatment and ICU admission.

Results
Complete records were available for 8,666 cases (36% of admissions statewide). 1,996 cases were included in the analysis, of which 908 were treated with RDV. 83% of cases were residents of the 7-county metro area of Minneapolis-St. Paul. Mean age was 59.7 years (IQR 48-72), 55% were male, and the mean RDV treatment duration was 4.8 days (range 2-15). The proportion of cardiovascular disease (30.6% vs 23.9%, p=.003), renal disease (16.6% vs 7.6%, p&lt; .001), and diabetes (34.7% vs 29.5%, p=0.01) was higher in the RDV untreated group, while obesity (22.3% vs 8.4%, p&lt; .001) and dexamethasone use (54.7% vs 15%, p&lt; .001) was more common in the RDV treated group. RDV untreated patients were more likely to be admitted to an ICU (18% vs 8.9%, p&lt; .001) and had higher inpatient mortality than those treated with RDV (11% vs 4.4%, p&lt; .001). After adjustment for dexamethasone use, age, sex and diabetes, treatment with RDV was associated with 48% lower odds of ICU admission (OR 0.52, 0.39-0.7, p&lt; .001).

Conclusion
We found RDV treatment associated with a significantly lower risk of ICU admission in patients admitted to hospital requiring supplemental oxygen, suggesting that treatment may prevent disease progression in this group. Further studies should assess the potential benefit of RDV combination treatment with dexamethasone.

Disclosures
Ruth Lynfield, MD, Nothing to disclose
528. Hospital Course of Patients Receiving Bamalanivimab: A Real World Analysis
Authors: Belk Madeline , Edwards Jonathan , Hassoun Ali 
Published: December 2021

Abstract

Background
Monoclonal antibodies for the outpatient treatment of the novel Coronavirus Disease 2019 (COVID-19) first received emergency use authorization from the Food and Drug Administration in November 2020. These antibodies have been associated with a reduction in emergency department visits and hospitalization through randomized controlled trials. However, modest data is available to describe the outcomes of patients who were hospitalized despite treatment. This study describes real-world outcomes concerning the treatment of COVID-19 with the first approved monoclonal antibody for COVID-19, bamlanivimab, as well as hospital courses associated with patients admitting after receiving the therapy.

Methods
This single-center, retrospective study evaluated real-world data of patients treated with bamlanivimab. The primary endpoint was a composite of emergency department (ED) visits or hospitalization due to worsening COVID-19. Data was analyzed from November 23, 2020 to March 5, 2021. Descriptive statistics were used to analyze the primary endpoint. Secondary endpoints include reported symptoms 24-hours post-infusion and time to symptom resolution in days. Additionally, clinical course of patients hospitalized were analyzed and include average oxygen requirements, median length of stay, and mortality. A subgroup analysis was conducted between patients less than sixty-five years of age and those sixty-five and older.

Results
619 patients received bamlanivimab during the specified timeframe. The primary endpoint occurred in 34 patients; 11 ED visits and 23 hospitalizations. Baseline characteristics of the patients hospitalized include median age 69 years (IQR 55, 74), 56.5% male, and 82.6% Caucasian. The most common risk factors for severe disease among those hospitalized were age ≥ 65 years and history of diabetes. The clinical course of hospitalized patients varied but 52.9% required nasal cannula for respiratory support and the average length of stay was 4.5 + 4.5 days. Other COVID-19 therapies included dexamethasone in 76.5% of patients and remdesivir in 47.1% of patients. There were no major differences in the subgroup analysis.

Conclusion
Bamlanivimab appears to attenuate the clinical course of COVID-19 in patients who are hospitalized despite treatment.

Disclosures
All Authors: No reported disclosures
529. Systematic Review and Meta-Analysis of Ivermectin Safety Profile in COVID-19 Trials
Authors: Wentzel Hannah , Wang Junzheng , Dayanamby Abbienaya , Pilkington Victoria , Levi Jacob , Hill Andrew , Ellis Leah 
Published: December 2021

Abstract

Background
There is a continued and pressing need for safe and effective treatment of COVID-19. Significant survival benefits have been shown by dexamethasone, tocilizumab and sarilumab, however they are only recommended in hospitalised COVID-19 patients. Ivermectin is a well-established and readily available antiparasitic drug which may be suitable for treatment in mild and moderate disease stages. It recently demonstrated anti-viral properties in vitro and now over 80 clinical trials have been registered worldwide to test its effectiveness in COVID-19 patients. This meta-analysis aims to collect data on adverse events reported in new COVID-19 treatment trials for the use of ivermectin as a repurposed medication.

Methods
Data was extracted from randomised trials of COVID-19 treatment trials identified through systematic searches of PUBMED, EMBASE, MedRxiv and trial registries. The primary outcome of this meta-analysis is the frequency of adverse events. Key safety events included serious, gastrointestinal, neurological, cardiovascular and dermatological adverse events.

Results
Overall, 18 trials investigating ivermectin for COVID-19 in a total of 2496 participants reported safety data and were included. There was no significant difference in the proportion of all adverse events between ivermectin and the comparator. There were 371/1261 (29%) adverse events recorded in the ivermectin containing arms and 376/1284 (29%) in the control arms (RR 1.02 [95% CI 0.77 - 1.34]; p = 0.91). There was no significant difference in the rate of serious adverse events across treatment arms (RR 1.95 [95% CI 0.75 - 5.11]; p = 0.18). No significant differences between ivermectin and the control were seen across different subcategories of adverse events. Figure 1 shows a summary of the results for all adverse events.

Forest plot comparing ivermectin and the control for all adverse events in COVID-19 trials, subdivided into single-day dosing trials and multi-day dosing trials.

Conclusion
The results of recent COVID-19 trials show that overall, ivermectin is safe and well-tolerated. No significant difference in adverse event reporting was found across all subgroups in single and multi-day treatment regimens for the studies analysed. Safety reporting methodologies often varied across trials. Future and ongoing trials should be encouraged to collect and monitor safety data systematically.

Disclosures
All Authors: No reported disclosures