COVID-19 Pharmacotherapy Effectiveness in the VA Healthcare System (COPE-VA)

CSP #2038 - COVID-19 Pharmacotherapy Effectiveness in the VA Healthcare System (COPE-VA)

The purpose of this study is to comprehensively describe the temporal and geographic utilization of COVID-19 therapies used for mild to moderate disease during different periods of SARS-CoV-2 variant circulation as well as to compare demographic and clinical characteristics of Veterans who are treated or do not receive these different therapies. The investigators will also perform similar descriptive epidemiology for other respiratory viruses, including RSV and influenza and other infectious diseases. This first phase will critically inform feasibility and direction of the second phase, in which the investigators will use target trial emulation design to study the comparative effectiveness of therapies and vaccines for COVID-19, respiratory viruses, including RSV, and influenza, and other infectious diseases.

Study Overview

• Status: Recruiting
• Conditions: Influenza; RSV; COVID-19, SARS-CoV-2 Infection

Detailed Description

Objectives:

This study will be completed in two phases. In the first phase, the investigators will establish a source population and comprehensively describe the temporal and geographic utilization of COVID-19 pharmacotherapies beginning July 2021. These therapies include casirivimab and imdevimab, bamlanivimab and etesevimab, sotrovimab, nirmatrelvir, molnupiravir, and remdesivir. The investigators will also compare demographic and clinical characteristics of Veterans who are treated or do not receive these therapies. Phase 1 will inform the study design and analytic protocol of Phase 2. Phase 1 will also inform critical policy questions and national guidance regarding COVID-19 pharmacotherapies in the VA healthcare system with the potential to inform policy across other healthcare systems.

In the second phase, the investigators will conduct target trial emulation studies to determine the effectiveness and comparative effectiveness of current pharmacotherapies for COVID-19 in preventing short- and long-term adverse outcomes related to SARS-CoV-2 infection. The investigators will use a sequence of comparative effectiveness studies through emulation to help establish a common framework sharing a similar population, design, and outcomes for a rapid-response, adaptive observational study design to characterize utilization and determine the effectiveness and comparative effectiveness of novel therapeutic agents authorized for the treatment of mild to moderate COVID-19 in Veterans. Phase 2 will provide an infrastructure upon which subsequent observational studies can be performed, which will include other infectious diseases of interest, ultimately ensuring the timeliness and pertinence of VA research.

Research Design and Methodology:

In the first phase, the investigators will conduct a descriptive, retrospective, electronic health record-based study among Veterans aged 18 years with a laboratory-confirmed positive test for SARS-CoV-2 or a diagnosis of COVID-19 documented at any time since the beginning of the pandemic in January 2020 to present. The investigators will describe the geographic distribution (by VISN, state, and distance from place of residence to the closest VAMC and/ COVID-19 infusion facilities) of Veterans receiving each of the COVID-19 antiviral and monoclonal antibody therapies during different periods of SARS-CoV-2 variant circulation (i.e., January 1, 2022, to present for Omicron). The investigators will also compare baseline demographic characteristics, clinical characteristics including underlying medical conditions and prior SARS-CoV-2 infections, SARS-CoV-2 vaccination status, National Institutes of Health (NIH) risk group tiers for prioritization of treatments, concurrent outpatient medications, and time from positive test to treatment among Veterans receiving different antiviral and monoclonal antibody therapies as well as eligible Veterans who are not treated during different periods of SARS-CoV-2 variant circulation. This established framework will also be used to identify Veterans who tested positive for other respiratory viruses, including influenza virus or respiratory syncytial virus (RSV), and other infectious diseases in the same time period and describe their characteristics, risk factors and treatments.

In the second phase, the investigators will conduct retrospective and prospective target trial emulation studies to evaluate the effectiveness and comparative effectiveness of different pharmacotherapies for mild-to-moderate COVID-19 in patients with documented SARS-CoV-2 infection by period of predominant SARS-CoV-2 variant circulation. The established framework will be used to investigate vaccine and pharmacotherapy effectiveness for SARS-CoV-2 and other respiratory viruses, including influenza and respiratory syncytial virus (RSV) and other infectious diseases using observational data from the VHA electronic health records.

Impact Significance:

Data on real-world utilization and clinical outcomes in the Veteran population are needed to inform clinical, operational and research partners in the VA and other healthcare systems on strategies for optimizing the utilization of pharmacotherapies and vaccines against COVID-19 and other infectious diseases. Ongoing evaluations will be essential as new variants emerge, vaccination practices evolve, and new pharmacotherapies are introduced. This study will establish a common framework sharing a similar population, design, and outcomes for a rapid-response, adaptive platform observational study design to characterize utilization and determine the effectiveness and comparative effectiveness of novel therapeutic agents authorized for the treatment of mild to moderate COVID-19, respiratory viruses, including RSV and influenza, and other infectious diseases in Veterans.

• Study Type: Observational
• Enrollment (Estimated): 400000

Contacts and Locations

• Study Contact: Name: George N Ioannou, MD MS; Phone Number: (206) 277-3136; Email: George.Ioannou@va.gov
• Study Contact Backup: Name: Kristina L Bajema, MD; Phone Number: (503) 220-8262; Email: Kristina.Bajema@va.gov

Study Locations

• United States
  • Oregon
    • Portland, Oregon, United States, 97207-2964
      • Recruiting
      • VA Portland Health Care System, Portland, OR
      • Contact: George N Ioannou, MD MS; Phone Number: (206) 277-3136; Email: George.Ioannou@va.gov
      • Contact: Kristina L Bajema, MD; Phone Number: 503-220-8262; Email: Kristina.Bajema@va.gov
      • Study Chair: Kristina L Bajema, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

VA enrollees infected from January 1, 2022 through February 28, 2022 as an example. Subsequent trials will be executed as the pandemic evolves

Description

Inclusion Criteria:

Phase 1:

- Veterans aged 18 years with a laboratory-confirmed positive test for SARS-CoV-2 or a diagnosis of COVID-19 documented at any time since the beginning of the pandemic in January 2020 to present.

Phase 2:

• All Veterans aged 18 years alive and in VHA care as of January 2018.
• Specific exclusion/inclusion criteria and observation periods will be further defined for each sub-study (See outcomes/publications).

Exclusion Criteria:

• VA employees who are not enrollees

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Outpatient Veterans with risk factors for severe COVID-19 & tested positive during Jan-Feb 2022; This cohort study assessed outpatient Veterans with risk factors for severe COVID-19 who tested positive for SARS-CoV-2 during January and February 2022. The purpose is to describe factors associated with receipt of outpatient COVID-19 pharmacotherapies in the Veterans Affairs (VA) health care system.
Nonhospitalized Veterans in VHA at risk for SARS-CoV-2 Jan-Jul 2022; Three retrospective target trial emulation studies comparing matched cohorts of nirmatrelvir-ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir- ritonavir versus molnupiravir. The purpose is to measure the effectiveness of nirmatrelvir-ritonavir and molnupiravir for outpatient treatment of COVID-19.
Outpatient Veterans who tested positive for SARS-CoV-2 from Jan 2022 through Jan 2023; This cohort study evaluated nonhospitalized Veterans in VHA care who tested positive for SARS-CoV-2 from January 2022 through January 2023 using VHA and linked Community Care and Medicare databases. The purpose is to analyze trends and factors associated with prescription of outpatient COVID-19 pharmacotherapies within the Veterans Health Administration (VHA).
Outpatient Veterans with risk factors for severe COVID-19 & tested positive during Jan-Jul 2022; Retrospective target trial emulation study comparing matched cohorts receiving nirmatrelvir-ritonavir versus no treatment. The purpose is to measure the effectiveness of outpatient treatment of COVID-19 with nirmatrelvir-ritonavir in preventing Post COVID conditions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Receipt of any COVID-19 pharmacotherapy, including sotrovimab, nirmatrelvir boosted with ritonavir, molnupiravir, or remdesivir	The odds of receipt of any COVID-19 pharmacotherapy, including sotrovimab, nirmatrelvir boosted with ritonavir, molnupiravir, or remdesivir were estimated using multivariable logistic regression	January and February 2022
Incidence of any hospitalization or all-cause mortality at 30 days and from 31 to 180 days	Three retrospective target trial emulation studies comparing matched cohorts of nirmatrelvir-ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir- ritonavir versus molnupiravir.	January through July 2022
Monthly receipt of any COVID-19 pharmacotherapy (nirmatrelvir-ritonavir, molnupiravir, sotrovimab, or bebtelovimab)	To analyze trends and factors associated with prescription of outpatient COVID-19 pharmacotherapies within the Veterans Health Administration (VHA).	January 2022 through January 2023
Cumulative incidence of 31 potential PCCs at 31 -180 days after treatment or a matched index date, including cardiac, pulmonary, renal, thromboembolic, gastrointestinal, neurologic, mental health, musculoskeletal, endocrine, and general conditions	Retrospective target trial emulation study comparing matched cohorts receiving nirmatrelvir-ritonavir versus no treatment.	January through July 2022

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Collaborators: Food and Drug Administration (FDA); Biomedical Advanced Research and Development Authority
• Investigators: Study Chair: George N. Ioannou, MD MS, VA Puget Sound Health Care System Seattle Division, Seattle, WA; Study Chair: Kristina L Bajema, MD, VA Portland Health Care System, Portland, OR

Publications and helpful links

General Publications

• Bajema KL, Berry K, Streja E, Rajeevan N, Li Y, Mutalik P, Yan L, Cunningham F, Hynes DM, Rowneki M, Bohnert A, Boyko EJ, Iwashyna TJ, Maciejewski ML, Osborne TF, Viglianti EM, Aslan M, Huang GD, Ioannou GN. Effectiveness of COVID-19 Treatment With Nirmatrelvir-Ritonavir or Molnupiravir Among U.S. Veterans: Target Trial Emulation Studies With One-Month and Six-Month Outcomes. Ann Intern Med. 2023 Jun;176(6):807-816. doi: 10.7326/M22-3565. Epub 2023 Jun 6.
• Bajema KL, Wang XQ, Hynes DM, Rowneki M, Hickok A, Cunningham F, Bohnert A, Boyko EJ, Iwashyna TJ, Maciejewski ML, Viglianti EM, Streja E, Yan L, Aslan M, Huang GD, Ioannou GN. Early Adoption of Anti-SARS-CoV-2 Pharmacotherapies Among US Veterans With Mild to Moderate COVID-19, January and February 2022. JAMA Netw Open. 2022 Nov 1;5(11):e2241434. doi: 10.1001/jamanetworkopen.2022.41434.
• Yan L, Streja E, Li Y, Rajeevan N, Rowneki M, Berry K, Hynes DM, Cunningham F, Huang GD, Aslan M, Ioannou GN, Bajema KL. Anti-SARS-CoV-2 Pharmacotherapies Among Nonhospitalized US Veterans, January 2022 to January 2023. JAMA Netw Open. 2023 Aug 1;6(8):e2331249. doi: 10.1001/jamanetworkopen.2023.31249. Erratum In: JAMA Netw Open. 2023 Oct 2;6(10):e2340494.
• Ioannou GN, Berry K, Rajeevan N, Li Y, Mutalik P, Yan L, Bui D, Cunningham F, Hynes DM, Rowneki M, Bohnert A, Boyko EJ, Iwashyna TJ, Maciejewski ML, Osborne TF, Viglianti EM, Aslan M, Huang GD, Bajema KL. Effectiveness of Nirmatrelvir-Ritonavir Against the Development of Post-COVID-19 Conditions Among U.S. Veterans : A Target Trial Emulation. Ann Intern Med. 2023 Nov;176(11):1486-1497. doi: 10.7326/M23-1394. Epub 2023 Oct 31.

Study record dates

Study Major Dates

• Study Start (Actual): September 26, 2022
• Primary Completion (Estimated): September 30, 2025
• Study Completion (Estimated): September 30, 2027

Study Registration Dates

• First Submitted: November 24, 2023
• First Submitted That Met QC Criteria: December 5, 2023
• First Posted (Actual): December 7, 2023

Study Record Updates

• Last Update Posted (Actual): January 24, 2024
• Last Update Submitted That Met QC Criteria: January 22, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: SARS-CoV-2; influenza; COVID-19; RSV; antiviral; respiratory viruses; pharmacotherapy effectiveness
• 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
• Other Study ID Numbers: 2038

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There is not a plan to make IPD available

Drug and device information, study documents

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