UPMC OPTIMISE-C19 Trial, a COVID-19 Study (OPTIMISE-C19)

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

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.

Study Overview

• Status: Terminated
• Conditions: Covid19
• Intervention / Treatment: Biological: Lilly Bamlanivimab; Biological: Regeneron Casirivimab + Imdevimab; Biological: Lilly Bamlanivimab + Etesevimab; Biological: Sotrovimab; Biological: Bebtelovimab

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.

• Study Type: Interventional
• Enrollment (Actual): 4571
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 120 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lilly Bamlanivimab; 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; Administration of Lilly Bamlanivimab to COVID positive patients
Experimental: Regeneron Casirivimab + Imdevimab; 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; Administration of Regeneron Casirivimab + Imdevimab to COVID positive patients
Experimental: Lilly Bamlanivimab + Etesevimab; 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; Administration of Lilly Bamlanivimab + Etesevimab to COVID positive patients
Experimental: Sotrovimab; 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; Administration of Sotrovimab to COVID positive patients
Experimental: Bebtelovimab; 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; Administration of Bebtelovimab to COVID positive patients

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

Collaborators and Investigators

• Sponsor: Erin McCreary
• Collaborators: University of Pittsburgh
• Investigators: Study Director: Erin McCreary, PharmD, University of Pittsburgh; Principal Investigator: David T Huang, MD, MPH, University of Pittsburgh

Publications and helpful links

General Publications

• Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.
• Hirsch C, Park YS, Piechotta V, Chai KL, Estcourt LJ, Monsef I, Salomon S, Wood EM, So-Osman C, McQuilten Z, Spinner CD, Malin JJ, Stegemann M, Skoetz N, Kreuzberger N. SARS-CoV-2-neutralising monoclonal antibodies to prevent COVID-19. Cochrane Database Syst Rev. 2022 Jun 17;6(6):CD014945. doi: 10.1002/14651858.CD014945.pub2.
• Huang DT, McCreary EK, Bariola JR, Minnier TE, Wadas RJ, Shovel JA, Albin D, Marroquin OC, Kip KE, Collins K, Schmidhofer M, Wisniewski MK, Nace DA, Sullivan C, Axe M, Meyers R, Weissman A, Garrard W, Peck-Palmer OM, Wells A, Bart RD, Yang A, Berry LR, Berry S, Crawford AM, McGlothlin A, Khadem T, Linstrum K, Montgomery SK, Ricketts D, Kennedy JN, Pidro CJ, Nakayama A, Zapf RL, Kip PL, Haidar G, Snyder GM, McVerry BJ, Yealy DM, Angus DC, Seymour CW. Effectiveness of Casirivimab-Imdevimab and Sotrovimab During a SARS-CoV-2 Delta Variant Surge: A Cohort Study and Randomized Comparative Effectiveness Trial. JAMA Netw Open. 2022 Jul 1;5(7):e2220957. doi: 10.1001/jamanetworkopen.2022.20957.
• McCreary EK, Bariola JR, Minnier TE, Wadas RJ, Shovel JA, Albin D, Marroquin OC, Kip KE, Collins K, Schmidhofer M, Wisniewski MK, Nace DA, Sullivan C, Axe M, Meyers R, Weissman A, Garrard W, Peck-Palmer OM, Wells A, Bart RD, Yang A, Berry LR, Berry S, Crawford AM, McGlothlin A, Khadem T, Linstrum K, Montgomery SK, Ricketts D, Kennedy JN, Pidro CJ, Haidar G, Snyder GM, McVerry BJ, Yealy DM, Angus DC, Nakayama A, Zapf RL, Kip PL, Seymour CW, Huang DT. The comparative effectiveness of COVID-19 monoclonal antibodies: A learning health system randomized clinical trial. Contemp Clin Trials. 2022 Aug;119:106822. doi: 10.1016/j.cct.2022.106822. Epub 2022 Jun 11.
• Huang DT, McCreary EK, Bariola JR, Wadas RJ, Kip KE, Marroquin OC, Koscumb S, Collins K, Shovel JA, Schmidhofer M, Wisniewski MK, Sullivan C, Yealy DM, Axe M, Nace DA, Haidar G, Khadem T, Linstrum K, Snyder GM, Seymour CW, Montgomery SK, McVerry BJ, Berry L, Berry S, Meyers R, Weissman A, Peck-Palmer OM, Wells A, Bart R, Albin DL, Minnier T, Angus DC. The UPMC OPTIMISE-C19 (OPtimizing Treatment and Impact of Monoclonal antIbodieS through Evaluation for COVID-19) trial: a structured summary of a study protocol for an open-label, pragmatic, comparative effectiveness platform trial with response-adaptive randomization. Trials. 2021 May 25;22(1):363. doi: 10.1186/s13063-021-05316-3.

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2021
• Primary Completion (Actual): June 16, 2022
• Study Completion (Actual): June 16, 2022

Study Registration Dates

• First Submitted: February 26, 2021
• First Submitted That Met QC Criteria: March 8, 2021
• First Posted (Actual): March 10, 2021

Study Record Updates

• Last Update Posted (Actual): June 15, 2023
• Last Update Submitted That Met QC Criteria: May 21, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: COVID; monoclonal antibodies
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Anti-Infective Agents; Antiviral Agents; Bamlanivimab; Sotrovimab; Casirivimab and imdevimab drug combination
• Other Study ID Numbers: STUDY21020179

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified participant-level data underlying the results reported in journal articles, subject to appropriate security controls, may be available for sharing with other researchers.
• IPD Sharing Time Frame: Relevant data may be available 1 year following publication
• IPD Sharing Access Criteria: Data access is subject to a methodologically sound proposal and the necessary data sharing agreements.
• IPD Sharing Supporting Information Type: SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No