Regional effects on efficacy and safety of vilobelimab in mechanically ventilated patients with severe COVID-19

Introduction: Poor outcomes in COVID-19 patients (pt) are associated with C5a-C5aR axis activation. A C5a-specific monoclonal antibody, vilobelimab (VILO), improves outcomes in critically ill COVID-19 pt in a Phase 3 randomized, double-blind, placebo (PLC)- controlled study [1]. Method(s): COVID-19 pt within 48 h of intubation were randomly assigned to receive 6, 800 mg infusions of VILO or PLC at a 1:1 ratio on top of standard of care. Predefined subgroup analyses by region and country were performed. Result(s): Forty-six (46) hospitals on 4 continents randomized 369 pt: VILO (n = 178), PLC (n = 191). VILO significantly reduced 28- (HR 0.67;95% CI 0.48-0.96;p = 0.027) and 60-Day mortality (HR 0.67;95% CI 0.48-0.93, p = 0.0163) using a predefined, unstratified per protocol analysis. Mortality rates at 28- and 60-days and VILO treatment effects, however, differed substantially between regions: Western Europe HR for 60-day mortality 0.59 [0.37-0.95], South Africa plus Russian Federation HR 0.62 [0.28-1.38] and South America HR 0.80 [0.46-1.39] (Fig. 1). The weak signal in South America is predominately driven by Brazil (n = 74), which showed a significant age imbalance with a median 9-years younger PLC group (44.5-years-old vs 53.5-years-old) with low 60-day mortality of ~ 32.5% in the PLC group versus ~ 43.3% in Western Europe. Adjusting for age group categories (<= 30, 31-40, 41-50, 51-60, > 60;Cox regression) for 60-day mortality changed the HR in Brazil (0.96 [0.44-2.10] for continuous age-adjustment) to values near the estimate for the entire study population (HR 0.77 [0.35-1.69] for age in categories), suggesting a by chance imbalance and not a statistically evident weaker effect in Brazil. Conclusion(s): Regional efficacy differences between the rest of the world and South America were driven by age imbalances between treatment groups, which do not diminish the robust efficacy signal for VILO in severe COVID-19.

Pharmacokinetic/pharmacodynamic analysis of vilobelimab and anaphylatoxin c5a as well as antidrug antibodies in Panamo: a phase 3 study in critically ill, mechanically ventilated COVID-19 patients

Introduction: C5a-C5aR axis activation is associated with increased mortality in severe COVID-19. Vilobelimab (VILO), a C5a-specific monoclonal antibody, improved mortality in severe COVID-19 patients (pts) in a Phase 3 multicenter, randomized, double-blind, placebo (PLC)- controlled study [1]. A pharmacokinetic/pharmacodynamic (PK/PD) analysis was undertaken to assess VILO and C5a as well as antidrug antibodies (ADA) levels in the study. Method(s): Forty-six (46) hospitals on four continents randomized 369 COVID-19 pts (VILO [n = 178], PLC [n = 191]) within 48 h of being mechanically ventilated to receive 6, 800 mg infusions of VILO or PLC at a 1:1 ratio on top of standard of care. Blood samples were taken at screening, Day 8 and at hospital discharge for VILO and C5a and at screening and hospital discharge for ADA. Enzyme-linked immunosorbent assays were used to analyze levels. Result(s): Screening blood samples for VILO and C5a were available for VILO (n = 93) and PLC (n = 99) from sites in Western Europe. On Day 8 after 3 infusions, mean VILO trough concentrations were 21799.3- 302972.1 ng/mL (geometric mean 137881.3 ng/mL) (Fig. 1). At screening, C5a was highly elevated and comparable between groups: VILO median 118.3 ng/mL, mean 130.3 ng/mL, PLC median 104.6 ng/mL, mean 123.2 ng/mL. By Day 8, C5a levels were reduced by 84.6% in the VILO group (median 14.5 ng/mL [mean 16.8 ng/mL], p < 0.001) versus a 19.6% increase in the PLC group (median, 119.2 ng/mL, mean 129.8 ng/ mL). Beyond Day 8, though PD sampling was sparse, C5a levels remained elevated for PLC whereas C5a slowly rose but did not reach screening levels for VILO. Treatment-induced ADA were observed in 1 pt in the VILO group (Day 40 discharge) and 1 pt in the PLC group (Day 25 discharge), both appeared independent of treatment. Conclusion(s): The PK/PD analysis shows that VILO efficiently inhibits C5a in pts with severe COVID-19 resulting in a robust clinical effect on mortality reduction without inducing ADA.

Emergency Department-based monoclonal antibody therapy for patients with mild to moderate COVID-19

Objectives: To describe the implementation of an ED-based program to offer monoclonal antibody therapy to patients with mild-moderate COVID-19 disease. Background(s): Monoclonal antibody therapy (MOAB) has recently emerged as a treatment for mild to moderate COVID-19, potentially preventing those with underlying conditions from progressing to severe illness and hospitalization. Further, as EDs are the primary point of health care access for many at-risk individuals, offering MOAB in the ED may increase availability of treatment options for patients from traditionally underserved communities. Method(s): A retrospective chart review was conducted of patients 12 years and above who received treatment in our urban, academic, community hospital. Patients 12 years and older were screened for eligibility during ED visits or during follow-up calls providing positive test results. Staff was trained on specific consent, infusion, monitoring, and documentation procedures adherent to MOAB administration under the Emergency Use Authorization. Patients were contacted following MOAB and queried regarding symptom resolution and healthcare utilization. Data regarding patient demographics, ED course, and 7-day unscheduled visits were collected. Result(s): In this ongoing quality improvement initiative, from December 2020 to March 2021, there were 26,229 patient encounters at the pilot ED site. 84 patients were provided MOAB, 87% Bamlanivimab and 13% Bamlanivimab/Etesevimab. Patients had a mean age of 52.3 years (SD 24.4);21% were 12-17 years of age and 37% were >65 years old. 52% were male. 33% self-reported as Caucasian, 19% Black, 18% Asian/Pacific Islander, 21% as other, and 9% were unknown. 17% identified as Latinx. 19% of patients were insured by Medicaid, 36% Medicare, 39% commercially insured, and 6% were uninsured. Patients had symptoms a median of 3 days prior to MOAB. After age (46%), the most commonly reported eligibility criteria was obesity (20%), followed by hypertension (11%) and immunocompromised state (11%). 74% of infusions were administered during nights and weekends. No infusion reactions occurred. 8% returned to an ED within 7 days of MOAB, 5% were hospitalized. No patients required ICU admission or died. Conclusion(s): ED-based MOAB has been safely implemented and may be an effective treatment for patients with mild to moderate COVID-19. Health-system wide expansion of this program may provide opportunities to offer this life-saving therapy to underserved populations with poor access to care.Copyright © 2023

Phase 3 RCT of C5a-Specific Vilobelimab in Severe COVID-19 Pneumonia

Background: Blocking the C5a-C5aR axis in COVID-19 patients could improve outcomes by limiting myeloid cell infiltration in damaged organs and preventing excessive lung inflammation and endothelialitis. Aims and Objectives: Vilobelimab (VILO), an anti-C5a mAb that preserves the membrane attack complex (MAC), was tested in a Phase III adaptively designed multicenter, double-blind placebo (P)-controlled study for survival in critically ill COVID-19 patients. Method(s): COVID-19 pneumonia patients (N=369;VILO n=178, P n=191) within 48 hrs of intubation were randomly assigned to receive 6, 800 mg infusions of VILO or P on top of standard of care. Primary outcome was 28-day allcause mortality. Result(s): 28-day all-cause mortality was 31.7% VILO vs 41.6% P (Kaplan-Meier estimates;Cox regression site stratified, HR 0.73;95%CI:0.50-1.06;P=0.094) with a 22.7% relative mortality reduction to Day 60. In predefined primary outcome analysis without site stratification, VILO significantly reduced 28-day mortality (HR 0.67;95%CI:0.48-0.96;P=0.027);needed to treat number, 10 to save 1. VILO significantly reduced 28-day mortality in severe patients with baseline WHO ordinal scale score of 7 (n=237, HR 0.62;95%CI:0.40-0.95;P=0.028) or severe ARDS/PaO2/FiO2<=100 mmHg (n=98, HR 0.55;95%CI:0.30-0.98;P=0.044) or eGFR<60 mL/min/1.73m2 (n=108, HR 0.55;95%CI:0.31-0.96;P=0.036). Treatment emergent AEs were 90.9% VILO vs 91.0% P. Infections were comparable;VILO (62.9%), P (59.3%). Serious AEs were 58.9% VILO, 63.5% P. Conclusion(s): VILO reduced mortality at 28 to 60 days in severe COVID-19 pneumonia patients with no increase in infections suggesting the importance of targeting C5a while preserving MAC.

Randomized, Controlled Phase 3 Study of anti-C5a Vilobelimab's Effect on Mortality in Critically Ill COVID-19 Patients: A Therapy for Viral Pneumonia

Background. SARS-CoV-2 induces endothelial damage and activates the complement system. In severe COVID-19 patients, complement split factor C5a is highly elevated leading to inflammation that contributes to multiorgan failure. The anti-C5a monoclonal antibody, Vilobelimab (Vilo), which preserves the membrane attack complex (MAC), was investigated in an adaptively designed, randomized doubleblind, placebo (P)-controlled Phase 3 international multicenter study for survival in critically ill COVID-19 patients (pts). Methods. COVID-19 pneumonia pts (N=368;Vilo n=177, P n=191), mechanically ventilated within 48 hrs before treatment, received up to 6, 800 mg infusions of Vilo or P on top of standard of care. The primary and main secondary endpoints were 28-day (d) and 60-d all-cause mortality. Results. Pts enrolled in the study were on corticosteroids (97%) and anticoagulants (98%) as standard of care. A smaller proportion (20%) were either continuing or had taken immunomodulators such as tocilizumab and baricitinib prior to receiving Vilo. The 28-d all-cause mortality was 31.7% with Vilo vs 41.6% with P (Kaplan-Meier estimates;Cox regression site-stratified, HR 0.73;95% CI:0.50-1.06;P=0.094), representing a 23.8% relative mortality reduction. In predefined primary outcome analysis without site stratification, however, Vilo significantly reduced mortality at 28 (HR 0.67;95% CI:0.48-0.96;P=0.027) and 60 days (HR 0.67;95% CI:0.48-0.92;P=0.016). Vilo also significantly reduced 28-d mortality in more severe pts with baseline WHO ordinal scale score of 7 (n=237, HR 0.62;95% CI:0.40-0.95;P=0.028), severe ARDS/PaO2/FiO2 <= 100 mmHg (n=98, HR 0.55;95% CI:0.30-0.98;P=0.044) and eGFR < 60 mL/min/1.73m2 (n=108, HR 0.55;95% CI:0.31-0.96;P=0.036). Treatment-emergent AEs were 90.9% Vilo vs 91.0% P. Infections were comparable: Vilo 62.9%, P 59.3%. Infection incidence per 100 Pt days were equal. No meningococcal infections were reported. Serious AEs were 58.9% Vilo, 63.5% P. Conclusion. Vilo significantly reduced mortality at 28 and 60 days in critically ill COVID-19 pts with no increase in infections suggesting the importance of targeting C5a while preserving MAC. Vilo targets inflammation which may represent an approach to treat sepsis and ARDS caused by other respiratory viruses. (Figure Presented).

ADDRESSING SOCIAL ISOLATION IN NURSING HOMES DURING COVID-19 – QUALITATIVE DATA FROM A NATIONAL SURVEY

The COVID-19 pandemic had dramatic, sometimes devastating impacts on nursing homes, residents, and staff. Rapid deployment of innovative approaches to resident care was required even while under sustained distress. We collected textual responses to open-ended questions about COVID-19 experiences through a national nursing home survey of Directors of Nursing/Administrators in February-May 2022. We employed a stratified (by size and quality ratings) sample of 1,669 nursing homes. Response rate was 30%, and 51% of responders answered > 1 open-ended question. We conducted an iterative thematic qualitative analysis yielding 10 themes. Respondents described addressing social isolation using new technology;enlisting staff from across the nursing home [beyond-the-call effort, gifting of voluntary time], and new ways for residents to safely connect with family. Respondents felt severely limited by COVID regulations that seemed to ignore residents' mental health needs. The majority of respondents felt significant professional and personal impact of the pandemic experience: "The pandemic was the most stressful situation I have encountered in 26 years of nursing” – "What a toll it took on all us emotionally, physically, and mentality” – "Every day was a challenge and I felt hopeless” – Some respondents plan to quit: "I am now seeking other employment. It has been too much for too long and has directly affected my mental health.” Nursing homes reported extraordinary efforts put forth by administration and staff to meet the needs of residents. Efforts to retain nursing staff are needed given profound impacts of the pandemic on their personal and professional lives.

ADDRESSING SOCIAL ISOLATION IN NURSING HOMES DURING COVID-19: A NATIONAL SURVEY

COVID-19 related policies introduced extraordinary social disruption in nursing homes. In response to the unprecedented COVID-19 pandemic, congregated long term care living facilities attempted and/or implemented innovative intervention strategies to alleviate loneliness in residents. We surveyed Directors of Nursing/Administrators of 1,669 homes sampled in strata defined by size (number of beds 30–99, 100+) and quality ratings (1, 2–4, 5) between February-May 2022. The response rate was 30%. Almost 2/3rds of respondents completed it online and the rest via paper. Analyses included nonresponse survey weights to provide nationally representative results. Among a list of 17 situations that occurred, staff shortages was identified as extremely stressful by the majority. Staff were extremely stressed about doing more to meet resident needs and keeping up with rapidly changing regulations which often lacked clinical sense. One third of respondents were extremely concerned about their home's ability to meet residents' social needs before vaccines, dropping to 13% after vaccines. Nursing homes tried and perceived as most useful using technology (tablets, phones, emails), assigning staff as a family contact, and staff spending more time with residents. Nearly 60% were extremely concerned about staff burnout/mental health before vaccines and 40% remained extremely concerned after vaccines. Many nursing homes attempted to mitigate the harmful effects of social isolation during the pandemic, despite the stressful circumstances in which staff worked. The extent to which various approaches were implemented varied. While concerns about social isolation reduced after vaccines were available, administrators remain extremely concerned about staff burnout and mental health.

Comparing Cholecystectomy Day Case Rates during the pre-COVID and COVID Era at a Rural District General Hospital

Aims: 67 000 cholecystectomies performed every year in The UK and 92% are laparoscopic. 75% of operations should be done as day cases. National rates vary between 6-50% with The most successful centres at 70%. Our aim was to audit The day case rate at our Trust pre-COVID and compare it to during COVID. Method(s): A retrospective audit of patients identified via clinical coding who had an elective cholecystectomy at one hospital in The Trust between 1 December 2018 to 31 November 2019. During COVID we did a prospective audit of patients identified via Theatreman who had an elective cholecystectomy at The Trust's designated "Green Hospital" between 21 September 2020 to 21 December 2020. Data for all patients was collected from electronic discharge summaries, clinic letters and patient notes. Result(s): Pre-COVID our day case cholecystectomy rate was 73% compared to 54.7% during COVID. Pre-COVID conversion rate from planned day case to inpatient stay was 16.3% and during COVID The conversion rate increased to 44%. The waiting time for a cholecystectomy doubled during COVID to 26.3 weeks from 13.6 weeks pre-COVID. Average re-admission rate with symptomatic gallstones was 0.79 pre-COVID and 0.95 during COVID, with 64% of patients having at lEast one admission prior to surgery. The average length of stay pre-COVID was 0.75 days compared to 0.57 days during COVID. Summary: COVID adversely affected our day case cholecystectomy rates with resultant increased waiting times for Surgery and readmissions with symptomatic gallstones however The average length of hospital stay was reduced.

HIV and SARS-CoV-2 INFECTION among POSTPARTUM KENYAN WOMEN and THEIR INFANTS

Background: People living with HIV may have increased risk of SARS-CoV-2 infection and severe COVID-19. However, few studies have examined the risk and outcomes of SARS-CoV-2 infection specific to postpartum women living with HIV and their HIV-exposed, uninfected (HEU) infants. To address this gap, we compared incidence, risk factors, and symptomatology of SARS-CoV-2 infection among mother-infant pairs living with and without HIV. Methods: We conducted a nested study of healthy mothers and infants enrolled in a Nairobi, Kenya-based prospective cohort study. Women living with HIV were enrolled in the parent cohort only if on antiretroviral therapy (ART) for ≥6 months. SARS-CoV-2 serology was performed on plasma collected between 1 May-31 December 2020 to assess incidence of infection and duration of antibody detection. SARS-CoV-2 RNA PCR and sequencing was also conducted on stool from seropositive participants. Sociodemographic and clinical data were used to evaluate risk factors for SARS-CoV-2 with Cox regression and to assess symptomatic COVID-19 with generalized estimating equations. Results: Among 104 mothers (51 living with HIV, 53 HIV-uninfected) and 89 infants (41 HEU, 48 HIV-unexposed), SARS-CoV-2 seropositivity was 38% and 17%, respectively. Incidence of infection did not differ significantly between women living with HIV and HIV-uninfected women (Hazard Ratio [HR]=1.51, 95% CI:0.78-2.94) or HEU and HIV-unexposed infants (HR=1.48, 95% CI:0.54-4.09). Maternal SARS-CoV-2 substantially increased risk of infant infection, regardless of HIV exposure (HR=10.3, 95% CI:2.89-36.8). However, no other factors-including CD4 count and years on ART among women living with HIV-were associated with infection. Antibody levels waned below detection in ∼30% of mothers and infants after a mean of 6 and 5 months, respectively. Among seropositive participants, SARS-CoV-2 RNA was detected among 5 of 27 mothers (19%) and one of 13 infants (8%) with samples. Sequences recovered from 2 samples were related to circulating variants in Kenya in 2020. One-fifth of participants had mild to moderate symptoms, but there were no cases of severe COVID-19 or death. Conclusion: Our findings show there was a high risk of SARS-CoV-2 infection among postpartum Kenyan women and their infants in 2020, though this risk was not substantially increased for women with well-managed HIV and most cases were asymptomatic. Rapidly waning antibody responses suggest continued preventive measures are needed until vaccination is widely available.

The PBL Projects Webinars: A Pandemic Creates New Opportunities

When the 2020 Covid-19 pandemic prevented an in-person problem-based learning (PBL) workshop in 2020, the authors developed and presented a series of virtual photonics workshops hosted by the Optical Society (OSA). © 2021 The Author(s).

Robot assisted radical prostatectomy in the covid-19 era: Implementation of same day discharge protocol using enhanced recovery after surgery principles

INTRODUCTION AND OBJECTIVE: The COVID-19 pandemic has impacted the ability to treat patients with prostate cancer due to increases in COVID-19 related hospital admissions and limited hospital bed availability. Same-day discharge (SDD) has previously been established as safe in patients who undergo robot assisted radical prostatectomy (RARP). We present our experience in implementing a SDD protocol using enhanced recovery after surgery (ERAS) principles. METHODS: This is a retrospective review that included all patients who underwent RARP at our institution between 06/01/2019 and 07/01/2020. Patient were stratified into two cohorts based on when COVID-19 restrictions were implemented at our institution: Pre COVID- 19 era (06/01/2019-02/29/2020) and COVID-19 era (03/01/2020-07/01/ 2020). During the COVID-19 era, we implemented a protocol that supported SDD by minimizing opioid use, encouraging ambulation immediately after surgery, and early oral intake. Success of SDD was assessed and perioperative complications were compared between the cohorts. RESULTS: In 283 prostatectomies performed at our institution during this review, 83 (29.3%) were performed during the COVID-19 era. The pre COVID-19 era contained more patients who had cT1 disease (56.0% vs 20.5%) and less patients with >cT3 (10.5% vs 30.1%, p<0.001). Same-day discharge was successfull in 29 (34.9%) of patients in the COVID-19 era vs 13 (6.5%) in the pre COVID-19 era (p<0.001). In the most recent 3 months at our institution, SDD rates have continued to increase to 67.4%, with 100% success in the most recent month. Overall complication rates, including hospital readmission, emergency department visits, and telephone calls after surgery did not differ between cohorts (p>0.05). CONCLUSIONS: We present practice changes that permitted the surgical management of prostate cancer patients to continue in an era where hospital bed capacity is limited by using ERAS protocols to rapidly and safely increase the SDD rate after surgery. Implications of such changes can be significant on the institutional and healthcare system level.

Mentoring in palliative medicine in the time of COVID-19

Background and aim: The COVID-19 pandemic has had significant ramifications upon clinical medical education. Restrictions on in-person face-to-face meetings and the limited mentoring support from redeployed physicians have compromised mentoring relationships and jeopardised mentoring programs in palliative medicine. The evidenced success of combined novice, peer-, near-peer and electronic-mentoring (CNEP) and interprofessional mentoring (IPM), together with palliative medicine's emphasis on interprofessional teamwork for holistic patient care, suggest that the concurrent application of CNEP and IPM (CNEPIPM) may be effective in addressing the continued geographical and manpower constraints in palliative medicine training amidst the COVID- 19 pandemic. This study thus aims to assess the viability and suitability of a CNEP-IPM mentoring approach in palliative medicine. Methods: With little known about this form of mentoring, a systematic scoping review (SSR) was carried out studying published accounts of CNEP and IPM. The Systematic Evidence Based Approach (SEBA) was adopted to enhance the trustworthiness, transparency and reproducibility of SSRs. Results: A total of 15,121 abstracts were reviewed, 557 full text articles were evaluated, and 92 articles were included. Concurrent content and thematic analysis revealed 4 themes/categories: characteristics of CNEP and IPM, stages of CNEP and IPM, the roles of host organizations and assessment methods and criteria. Conclusions: This SSR evidences the viability of a CNEP-IPM approach and forwards an evidence-based framework for the design, implementation and evaluation of a CNEP-IPM mentoring program in palliative medicine. Further prospective studies and research into the program design, mentoring process, complex CNEP-IPM mentoring relationships, and the validation of robust evaluation tools are still required.

Physicians’ perceptions on the role of telemedicine in cancer care during and post-COVID-19 pandemic

Objectives. This study aims to determine perceptions of physicians in our institution on the role of telemedicine in cancer care during the COVID-19 pandemic and to assess its perceived benefits and barriers. Methods. This is a cross-sectional study of physicians involved in cancer care in a tertiary referral hospital in the Philippines. We administered a 21-item online survey questionnaire between August to October 2020. Results. We received and analyzed 84 physician responses. Ninety-six percent of physicians currently use telemedicine, an increase from 59% pre-pandemic. Eighty-nine percent use telemedicine for follow-up virtual consults, while 75% use telemedicine for case discussions in multidisciplinary meetings. The mean number of monthly patient consults conducted through telemedicine increased to 29.5 (SD: 24.8) from a pre-pandemic mean of 7.7 (SD: 18.7). Eighty-four percent of respondents perceived its main benefit as an infection control measure. The other perceived benefits of telemedicine include convenience (78%), accessibility to cancer care (72%), cost-effectiveness (68%), and time efficiency (44%). A quarter of the respondents believed that telemedicine has the potential to improve cancer outcomes. Ninety-two percent of the respondents expressed that they will use telemedicine occasionally in their practice. Conclusion. Telemedicine was perceived by Filipino physicians in a tertiary hospital as an acceptable solution for the provision of cancer care during and after the COVID-19 pandemic. Tele-oncology should be further investigated to maximize patient and physician satisfaction and improve cancer outcomes. Data from this study can be used to improve oncology practice and service delivery to suitable patients during and after the COVID-19 pandemic. © 2021 University of the Philippines Manila. All rights reserved.