Early-Phase Dose-Finding Trials in Virology

Viruses have taken central place in public health due to the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Antiviral treatments, and combination of antivirals, can be effective at reducing viral load shortly after infection, improving long-term outcomes. While it is obvious that choosing the right dose of treatment is a fundamental consideration, little has been published in terms of methodology for dose-finding trials in virology. The considerable progress in dose-finding methodology of the last few decades has focused almost entirely on oncology. However, the framework developed in oncology does not apply 1:1 to virology. While adverse reactions to cytotoxic drugs may be life threatening, for anti-viral agents, we anticipate something different: side effects that provoke the cessation of treatment. This would correspond to treatment failure. On the contrary, success would not be yes/no but would correspond to a range of responses, from small, no more than say 20% reduction in viral load to the complete elimination of the virus. Less than total success matters since this may allow the patient to achieve immunemediated clearance. In this presentation, we will introduce a novel methodology whose goal is twofold: first, to identify the dose that provides the most favorable distribution of treatment outcomes, and, second, to do this in a way that maximizes the treatment benefit for the patients included in the study. We will compare two modeling approaches in the talk. The first approach relies on the Bayesian Dirichlet-Categorical model to describe the toxicity/efficacy profile of each of the dose levels. The second approach relies on the principles of the continual reassessment model (CRM). We separately model the dose-toxicity curve and the dose-efficacy curve. By representing efficacy with three categories (low, medium, high viral load reduction), we can use the following assumptions: dose-efficacy curve is decreasing for the low-response category, and dose-efficacy curve in increasing for the high-response category. By combining the modeled toxicity and efficacy curves, we obtain the center of mass curve over the dose levels of interest. We will compare both approaches via simulations. The first approach described above has been recently published in Statistics in Medicine (doi: 10.1002/ sim.8771). The second approach is being currently developed and tested and will be the topic of a future publication.

A Decade of Educational Outreach by the MC3 Program: What Has Worked and What We Are Still Learning

Objectives: This presentation aims to describe the development, assessment, and sustainability of educational outreach materials and methods within the Michigan Child Care Collaborative (MC3) platform since its inception over 10 years ago. Method(s): Historical data and current content related to education of providers and trainees enrolled in the MC3 program will be reviewed. Provider feedback is requested after each session, and the frequency of topics requested and presented will be provided. A discussion of modalities that have transitioned over time, such as regular practice case conferences, will also be discussed. Result(s): Over the last 5 years, MC3 has offered several types of educational programming, including: live presentations (n = 81), conferences, provider cafes, and recorded modules (n = 40). Examples of the topics include the following: Depression and Suicide Screening, Caring for Transgender and Gender Questioning Youth, Perinatal Trauma and Stress, and Managing Children's Anxiety During the COVID-19 Pandemic. Comments and feedback provided following the provision of more tailored, community-specific programming, such as holding a day long Pediatric and Perinatal Conference in person for the Flint Community practices, will be discussed. Data related to provider feedback from live presentations and recorded educational modules will be presented to describe the perceived effectiveness by providers. Additional educational modalities, including the pediatric and perinatal psychopharmacology cards, and resources specific to COVID-19 and antiracism, will also be reviewed within the context of which platforms have been most accessible and sustainable to maintain. Conclusion(s): Providers value multiple modalities/learning platforms to supplement their experiences with individual, patient/case-based consultation. Providers appreciate having access to supplemental educational materials at any time through our web-based platform. Although virtual formatting allows us to extend our reach across the state, there are likely some limitations in terms of fostering more foundational relationships with some of the providers with whom we work. Ongoing community-specific collaborations have offered rich opportunities for collaboration, including work with the Inter-Tribal Health Authority and bidirectional cultural competency training. EBP, CON, CC Copyright © 2022

Comparison of Clinical and Thrombotic Outcomes in Sars-Cov-2- Pneumonia Versus Other Viral Pneumonia in an Urban Academic Medical Center

Title: Comparison of Clinical and Thrombotic Outcomes in SARS-CoV-2- Pneumonia versus Other Viral Pneumonia in an Urban Academic Medical Center Objective: To compare clinical and thrombotic outcomes in SARS-CoV-2 pneumonia versus other viral pneumonias. Introduction: Viral pneumonia (PNA) causes oxidative stress to the pulmonary vasculature, triggering endothelial dysfunction and activation of the coagulation cascade. Elevations in coagulation markers, including d-dimer and fibrinogen, have been observed. Recent studies indicate that SARS-CoV-2 infection causes endothelial cell injury, with activation of the coagulation cascade, and a high frequency of systemic thrombotic events. It remains unclear whether it is viral pneumonia itself, a specific viral strain (and/or viral load) that drives the clinical and thrombotic outcomes. Furthermore, limited data is available regarding clinical outcomes in a diverse patient population hospitalized with SARS-CoV-2 infection. This study is from a single urban medical center in Chicago, Illinois. Study Design: A retrospective cohort study evaluating the medical records of hospitalized adult patients admitted to University of Illinois Hospital and Health Sciences System (UIHHSS) with SARS-CoV-2 pneumonia or other viral (H1N1 or H3N2) pneumonia between 10/01/2017 and 09/01/2020. Methods: Patients were included if ≥18 years old, hospitalized, with a primary confirmed diagnosis of viral pneumonia (SARS-CoV-2, H1N1 or H3N2) based on ICD-10 code, viral diagnostic testing, diagnosis description, and appropriate clinical characteristics/imaging studies. Past medical history, inpatient medications, coagulation parameters, arterial/venous thrombotic outcomes, and other clinical outcomes (renal replacement therapy, mechanical ventilation, co-infection) were ed from UIHHSS electronic health record database. Results: Medical records of 257 patient with a primary diagnosis of pneumonia were reviewed, 199 patients with SARS-CoV-2 PNA (95 male, average age 58 years, 52% Hispanic, 37% non-Hispanic Black) and 58 patients with other viral PNA (24 male, average age 63 years, 21% Hispanic, 55% non-Hispanic Black;34 with H3N2, 24 with H1N1). Coagulation parameters (maximum D-dimer, fibrinogen, INR) were similar in both groups;average D-dimer was >3x ULN. Anticoagulation therapy was similarly prescribed in both groups (SARS-CoV-2, 95% vs 84%, H1N1 or H3N2), with prophylactic dose anticoagulation prescribed most frequently (73% vs 62%) and with high average compliance rates (89% vs 83%). Admission to the intensive care unit (ICU;32% vs 29%) and the median length of stay (10 vs 4 days) was similar in both groups. Thrombotic events (n = 6, 3%) occurred only in SARS-CoV-2 PNA patients in the ICU: 3 pulmonary embolism (PE), 1 distal lower extremity deep vein thrombosis (DVT), 2 non-ST elevated myocardial infarctions (NSTEMI). There was a significantly higher incidence of use of renal replacement therapy (8.5% vs 0%, p=0.016) and mortality (15.6% vs 3.4%, p=0.048) in the SARS-CoV-2 PNA group compared to the H3N2/H1N1 PNA group. There were no differences in the rates of mechanical ventilation, the incidence of major bleeding or co-infection. In a multivariable logistic regression analysis, age (aOR 1.07), the presence of SARS-CoV-2 PNA (aOR 11.37), and ICU admission (aOR 41.95) were significantly associated with risk of mortality during hospitalization. Race and ethnicity were not associated with mortality. Conclusion: The overall incidence of thrombotic events was low and occurred only in the SARS-CoV-2 PNA group. The low rate of venous thrombosis detected in this group, especially in the ICU setting, is likely related to the reduced use of diagnostic studies during the first COVID-19 pandemic in 2020 and to the high rates of anticoagulation prophylaxis orders and compliance. SARS-CoV-2 PNA was associated with a higher rate of renal failure and mortality compared to patients with H3N2/H1N1 viral pneumonia. There was no difference in mortality rates between Hispanic and non-Hispanic and between Black and non-Black patients. This study suggests that SARS-CoV-2 pneumonia leads to greater endothelial dysfunction than that observed in H3N2/H1N1 viral pneumonia and that race/ethnicity does not drive mortality outcomes. Disclosures: Benken: BMS: Research Funding;CareDx: Research Funding;Transplant Genomics: Research Funding;Daiichi Sankyo: Research Funding;Verici Dx: Research Funding.

MICHIGAN CHILD COLLABORATIVE CARE PROGRAM (MC3): TEN YEARS OF GROWTH, ADAPTATION, AND LEARNING

Objectives: This presentation aims to describe the unique opportunities and challenges encountered in the development and delivery of telepsychiatric consultation services through the Michigan Child Psychiatry Access Program (MC3). We will specifically address outreach to vulnerable populations, and to adaptations during the time of COVID-19. Methods: A review of existing program data will describe the populations served, number of consultations provided, naming of types of services offered, funding relationships, and current state of service delivery within the MC3 program. Results: Over the course of 10 years, the MC3 program has provided 8500 consultations to pediatric primary care and perinatal providers. Pilot programming has also included services to populations of specific need, particularly the children and families of Flint, and the Tribal Health Centers of Michigan. The most common diagnoses discussed are related to anxiety, depression, and ADHD. During 2020, approximately 30% of consultations were related to the impact of COVID-19. The rate of consultation during the initial period of the pandemic fell by 37% from the year prior, and beginning in November of 2020, the rate of consultation resumed to rates maintained prior to the pandemic. We will present more detailed demographic data on the sociodemographic representation of patients we consulted on during the pandemic time period. We will also describe additional education efforts that include 87 live and recorded educational presentations on a variety of topics. Conclusions: Scaffolding a telepsychiatry program such as MC3 requires significant foundational and ongoing resources. A dedicated staff, ongoing relationships with the existing community mental health infrastructure, and sustainable funding allow for this program to be responsive to the changing needs of a state’s population. Despite this, significant work remains to leverage this service as a tool to narrow healthcare disparities in child mental health. Responsive changes to data collection and direct engagement with local community mental health centers can allow for the identification of needs specific to certain populations, particularly during this time of the COVID-19 pandemic. CON, TVM, DEI

Phase Ib study of the safety and efficacy of Gemtuzumab Ozogamicin (GO) and Venetoclax in patients with relapsed or refractory CD33+ acute myeloid leukemia: Big Ten Cancer Research Consortium BTCRC-AML17-113

Background:AML is predominantly a disease of the elderly, yet outcomes remain dismal, particularly for relapsed/refractory (R/R) AML patients (pts). Gemtuzumab Ozogamicin (GO) is a monoclonal antibody targeting CD33-commonly expressed on AML blasts, and, critically, AML stem cells (LSC)-linked to the cytotoxin calicheamicin. GO resistance mechanisms include (i) decreased/aberrant blast CD33 expression, (ii) p-glycoprotein export of calicheamicin, and (iii) apoptosis resistance due to deficient activation of mitochondrial outer membrane permeabilization, a process highly dependent on BCL-2 expression. GO-induced apoptosis depends on the pro-apoptotic proteins Bax and Bak and is inhibited by overexpression of the anti-apoptotic proteins BCL-2 or BCL-XL. Venetoclax (VEN) is a BH3 mimetic, binding BCL-2, dislodging its binding to Bak/Bax, and thus facilitating apoptosis. LSC overexpress BCL-2, however VEN monotherapy is not effective in AML, as resistance develops rapidly. Hypothesis: VEN targeting of BCL-2 proteins that protect LSC from GO-induced apoptosis will synergistically increase GO efficacy. Correlative studies include pre-treatment AML blast BH3 profiling, CD33 expression (including sequencing for isoforms), and BCL-2, BCL-XL, and MCL-1 protein levels;MRD measurement at post-therapy time points using digital drop PCR technology;and quality of life assessments (EORTC QLQ-C30, FACT-Fatigue) MethodsThis is a single arm, open-label, multi-center (BTCRC), dose-escalation phase Ib study of combination of VEN and GO in R/R AML pts (18-75y), using a 3+3 design. Major eligibility: ECOG 0-2, adequate organ function, CD33+ in ≥ 20% AML blasts, ≤ 3 lines of prior therapy, and no prior use of GO or VEN, previous VOD, BMT within 2 months, CNS disease, or history of HIV. Induction: 3-day VEN ramp-up to the target dose of 200 (cohort i), 400 (ii), or 600 (iii) mg daily x 28 d, with GO 3mg/m2 infused days 1, 4, and 7. If CR/CRi achieved, pts proceed to BMT if applicable, otherwise, if in CR/CRi (provided ANC > 1000, plts > 100K) or PR (regardless of counts), they are consolidated with VEN at the prescribed dose x 28d and GO 3mg/m2 on days 1 and 4 (Cycle 2). If BMT not applicable, and pt remaining in CR/CRi or PR (as above), then proceed to VEN alone as Maintenance in cycles 3+ until progression or toxicity. The primary endpoint is MTD of VEN with GO. Secondary endpoints include ORR, antileukemic activity, characterization of AEs, and estimates of RFS, EFS, and OS. Progress: This study is currently open to its second dosing cohort and has enrolled 5 pts to date. No dose-limiting toxicities have been encountered. However, the COVID-19 pandemic has had a negative impact on enrollment, which is expected to improve as vaccinations expand. ClinicalTrials.gov NCT04070768.

Behaviour of occupational health services during the COVID-19 pandemic.

BACKGROUND: Disasters, crises and pandemics are emergencies which impact on businesses severely. The COVID-19 pandemic reached its peak in mid-April 2020 in the UK. During this period, NHS Occupational Health Services (OHS) were stretched to their limit along with other health services. OHS may have had to change their pattern of operation, operating times, services offered, etc. to cope with the pandemic. Data about business model modifications, services offered by the OHS businesses during the pandemic could help in better utilization of OHS resources in the future. AIMS: To understand the behaviour of OHS in different parts of the country during the COVID-19 pandemic. METHODS: An online survey link was sent to both accredited and unaccredited UK Occupational Health Physicians (OHPs). RESULTS: Sixty-two OHPs responded to the survey. In the current pandemic, 51% of the OHS (95% CI 0.38-0.62) offered weekend or out-of-hours (OOH) services, 21% had to employ extra staff (95% CI 0.13-0.33) and 54% had to change their working hours (95% CI 0.41-0.65). Ninety per cent of the OHS (95% CI 0.78-0.94) continued to offer routine services; however, there was a decline in offering vaccination services. Fifty-six per cent of the OHS (95% CI 0.42-0.67) offered a dedicated telephone line and 46% of the OHS (95% CI 0.32-0.56) started a dedicated COVID-19 queries inbox. CONCLUSIONS: There was a change in the behaviour of the OHS to cope with the pandemic. Having a dedicated helpline to manage the crisis situation seemed a logical step whilst offering routine services.