UPMC OPTIMISE-C19 Trial, a COVID-19 Study

Study Overview
=================
Brief Summary
-----------------
Multiple monoclonal antibodies (mABs) have been shown to reduce viral burden and improve clinical outcomes, have been granted FDA Emergency Use Authorization (EUA) for use in select populations, and are routinely used in the UPMC Health System, which has made expanded access a priority. However, the comparative effectiveness of these mABS is unknown. The National Academies of Sciences, Engineering, and Medicine has called for expanded access and clinical use of mABs, noting it is critical to collect data and evaluate whether they are working as predicted. This pragmatic evaluation will determine the relative effects of the EUA-governed mABs versus each other. When U.S. government mAB policies change (e.g., FDA grants or revokes EUAs), UPMC Health System policies and the evaluated mABs will accordingly change.

Detailed Description
-----------------
While COVID-19 vaccination will reduce COVID-19-related morbidity and mortality, the learned immune response may vary between individuals. This means interventions such as monoclonal antibodies (mAB) will still be needed to prevent progression of COVID-19 illness. Monoclonal antibodies seek to mimic or enhance the natural immune system response against a pathogen and are often used in the care of patients with cancer or infection. For viral infections, mABs are created by exposing a white blood cell to a particular viral protein, which is then cloned to mass produce antibodies to target that virus. For SARS-CoV-2, the virus that causes COVID-19, IgG1 mABs target the spike protein of SARS-CoV-2 and block viral attachment and entry into cells. The SARS-CoV-2 mABs bamlanivimab and etesevimab, and the REGN-COV2 combination (casirivimab + imdevimab) reduce nasopharyngeal viral burden plus clinical outcomes including future emergency department visits and hospitalizations. Each received FDA Emergency Use Authorization (EUA) for use in selected populations. As of February 2021, there are over 60,000 new cases of COVID-19 diagnosed daily in the US, with over 7000 daily COVID-19 related hospital admissions. Although case volumes are currently declining, COVID-19 remains a significant public health threat. Despite the EUAs, the clinical use of mABs is low due in part to lack of patient access, complexities in drug allocation, and lack of knowledge among providers are contributing factors. Further, the comparative effectiveness of different mABs is unknown and not yet directly studied. The National Academies of Sciences, Engineering, and Medicine recently called for expanded access and clinical use of mABs, noting it is critical to collect data and evaluate whether they are working as predicted. This evaluation seeks to determine their relative effects versus each other, starting with those governed by EUAs. OPTIMISE-C19 is a quality improvement (QI) study, governed by approvals from both the UPMC QI committee and the University of Pittsburgh IRB. Currently, mAB therapy is approved for use under EUA issued by the FDA. There are no data on the relative benefits of one mAB versus any other. mABs are ordered by UPMC physicians as a generic referral order and the order is filled by UPMC pharmacy via therapeutic interchange. The selection of mABs available within pharmacy is overseen by the UPMC pharmacy and therapeutics committee. OPTIMISE-C19 provides the therapeutic interchange via random allocation. The UPMC Quality Improvement Committee approved the OPTIMISE-C19 study, including the random therapeutic interchange. The University of Pittsburgh IRB considered the randomized therapeutic interchange to be quality improvement and approved the additional data collection and analyses. Patients provide verbal consent to receive mAB therapy. UPMC requires physicians to provide and review with patients the EUA Fact Sheet for each mAB, and explain that the patient could receive any of the EUA-governed mABs. As per EUA requirements, physicians discuss the risks and benefits of mABs with patients, and patients consent to receive a mAB as part of routine care, should they desire mAB treatment. Patients are told which mAB they are receiving, and physicians and patients can agree to the assigned mAB or request a specific mAB. It is the treating physicians' and patients' choice to accept the assigned mAB or not. The QI committee considered these steps to represent adequate consent to participate. The IRB considered that the provision of mAB therapy therefore fell under quality improvement and only the additional data collection and analyses represented research. The IRB waived any additional consent requirements.

Official Title
-----------------
The UPMC OPtimizing Treatment and Impact of Monocolonal antIbodieS Through Evaluation for COVID-19 Trial

Conditions
-----------------
Covid19

Intervention / Treatment
-----------------
* Biological: Lilly Bamlanivimab
* Biological: Regeneron Casirivimab + Imdevimab
* Biological: Lilly Bamlanivimab + Etesevimab
* Biological: Sotrovimab
* Biological: Bebtelovimab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: COVID-19 positive patients Eligible for mAB under FDA EUA Exclusion Criteria: Death is deemed to be imminent or inevitable Previous participation in this REMAP within the last 90 days

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 120 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study is an adaptive platform and as such is intended to study multiple interventions simultaneously, does not have a defined sample size, and is intended to move forward in perpetual fashion with domains and interventions being added and subtracted over time. For example, interventions will be added and subtracted depending on federal decisions regarding monoclonal antibodies, such as granting or revoking authorization for use.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lilly Bamlanivimab<br>The Lilly monoclonal antibody bamlanivimab will be administered according to FDA EUA guidelines. Dosing is 700 mg intravenously times one within 10 days of COVID-19 symptom onset. | Biological: Lilly Bamlanivimab<br>* Administration of Lilly Bamlanivimab to COVID positive patients<br>|
| Experimental: Regeneron Casirivimab + Imdevimab<br>The Regeneron monoclonal antibody cocktail Casirivimab + Imdevimab will be administered according to FDA EUA guidelines. Dosing is 1200 mg of each drug (2400 mg total) administered intravenously times one within 10 days of COVID-19 symptom onset. | Biological: Regeneron Casirivimab + Imdevimab<br>* Administration of Regeneron Casirivimab + Imdevimab to COVID positive patients<br>|
| Experimental: Lilly Bamlanivimab + Etesevimab<br>The Lilly monoclonal antibody cocktail of bamlanivimab + etesevimab will be administered according to FDA EUA guidelines. Dosing is given intravenously times one within 10 days of COVID-19 symptom onset. | Biological: Lilly Bamlanivimab + Etesevimab<br>* Administration of Lilly Bamlanivimab + Etesevimab to COVID positive patients<br>|
| Experimental: Sotrovimab<br>The monoclonal antibody of sotrovimab will be administered according to FDA EUA guidelines. Dosing is given intravenously times one within 7 days of COVID-19 symptom onset. | Biological: Sotrovimab<br>* Administration of Sotrovimab to COVID positive patients<br>|
| Experimental: Bebtelovimab<br>The monoclonal antibody of bebtelovimab will be administered according to FDA EUA guidelines. Dosing is given intravenously times one within 7 days of COVID-19 symptom onset. | Biological: Bebtelovimab<br>* Administration of Bebtelovimab to COVID positive patients<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospital-free Days | Days alive and free from hospitalization. Patients that are both living and not in the hospital will meet criteria to be counted in this outcome. Deaths were rare and therefore the upper and lower end of the IQR are both 28, in addition to the median. This outcome measure does reflect median hospital free days and interquartile ranges for all groups. | 28 days after initial participation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause Mortality at 28 Days | All-cause mortality at 28 days. | 28 days after initial participation | 
| SARS-CoV-2 Nasopharyngeal Viral Loads | Where feasible SARS-CoV-2 nasopharyngeal viral loads among participants from baseline and longitudinally through day 28 | 28 days after initial participation | 
| SARS-CoV-2 Plasma Viral Loads | Where feasible SARS-CoV-2 plasma viral loads among participants from baseline and longitudinally through day 28 | 28 days after initial participation | 
| SARS-CoV-2 Antibody Titers | Where feasible SARS-CoV-2 antibody titers at baseline and longitudinally through day 28 | 28 days after initial participation | 
| SARS-CoV-2 Antibody Neutralization | Where feasible SARS-CoV-2 antibody neutralization at baseline and longitudinally through day 28 | 28 days after initial participation | 
| SARS-CoV-2 Immune Responses | Where feasible SARS-CoV-2 immune responses at baseline and longitudinally through day 28 | 28 days after initial participation | 
| Detection of SARS-CoV-2 Variants Through Next-generation Sequencing | Where feasible detection of SARS-CoV-2 variants through next-generation sequencing at baseline and longitudinally through day 28 | 28 days after initial participation | 
| Duration of SAR-CoV-2 Infectivity | Where feasible determining the duration of SAR-CoV-2 infectivity among patients with persistent nasopharyngeal swab viral shedding | 28 days after initial participation | 
| Non-culture Surrogates for SARS-CoV-2 Infectivity | Where feasible determining non-culture surrogates for SARS-CoV-2 infectivity among patients with persistent nasopharyngeal swab viral shedding | 28 days after initial participation | 
| Non-culture Surrogates for SARS-CoV-2 Infectivity | Where feasible determining non-culture surrogates for SARS-CoV-2 infectivity among patients with persistent nasopharyngeal swab viral shedding | 90 days after initial participation | 
| Duration of SAR-CoV-2 Infectivity | Where feasible determining the duration of SAR-CoV-2 infectivity among patients with persistent nasopharyngeal swab viral shedding | 90 days after initial participation | 
| ED Visit Within 28 Days |  | Duration of study | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COVID, monoclonal antibodies