VA CoronavirUs Research and Efficacy Studies-1 (VACURES-1)

VA CoronavirUs Research and Efficacy Studies-1 (VA CURES-1)

The purpose of this study is to determine if treatment with convalescent plasma improves the clinical outcomes of Veterans who are hospitalized and require supplemental oxygen due to COVID-19.

Study Overview

• Status: Terminated
• Conditions: COVID-19
• Intervention / Treatment: Drug: Convalescent Plasma; Other: Masked Saline Placebo

Detailed Description

As of August 25, 2020, SARS-Coronavirus 2 (SARS-CoV-2; COVID-19) infections are approaching 6 million persons and 180,000 deaths in the US. Of the 20% of patients admitted to hospital, up to half progress to ICU admission, respiratory failure or death. Prominent among these progressors are older men, particularly those with underlying comorbidities (e.g., hypertension, diabetes, lung, heart, kidney or liver disease, obesity and immunocompromised), all common among Veterans. There are no drugs or other therapeutics approved by the FDA to prevent or treat COVID-19 infection.

Convalescent plasma therapy is being used empirically, although only five of six small uncontrolled case series (total n=56) in SARS-CoV-23-8 and a recent study with non-randomized controls suggest improved selected clinical, virologic and laboratory outcomes; outcomes in another small randomized trial were equivocal. For other infections, such as influenza and Ebola virus, promising observational studies were not reliably confirmed by controlled trials. In multiple infections, use of convalescent plasma has been distinguished by its safety profile but not by the consistency of its benefit.

The current double-blind, placebo-controlled randomized clinical trial (RCT) is designed to determine definitively whether this intervention is effective in a population at high risk of complications and death from SARS-CoV-2 infection. The investigators compare the effect of convalescent plasma vs. saline placebo with a robust study design, adequate sample size and statistical and logistical rigor to assure that the interventions the investigators make to treat serious disease are well-validated to support its use or to move on to test other potentially safe and effective treatments.

This study is taking place at approximately 25 Veterans Affairs (VA) Medical Centers located across the US. A participant's involvement will last up to 33 days. The entire study, from the date the first person enters until the last participant is seen, is expected to last about 20 months.

Data collected for this study will be analyzed and stored at the Palo Alto Cooperative Studies Program Coordinating Center (CSPCC). After the study is completed, the de-identified, archived data will continue to be stored at the Palo Alto CSPCC, accessible for use by researchers including those outside of the study with an approved Data Use Agreement. The biospecimens collected in the study for current and future research will be kept at the VA Biorepository in Palo Alto, California unless otherwise specified. The biospecimens will be accessible for future research with an approved Sample Use Agreement. The VA Central Institutional Review Board (CIRB) will oversee the biorepository for this study. All samples will be destroyed by standard practice within 20 years of study completion. Sample destruction will be validated according to the Standard Operating Procedures of the VA Biorepository.

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 3

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00921
    • VA Caribbean Healthcare System, San Juan, PR
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Birmingham VA Medical Center, Birmingham, AL
  • Arizona
    • Phoenix, Arizona, United States, 85012
      • Phoenix VA Health Care System, Phoenix, AZ
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Rocky Mountain Regional VA Medical Center, Aurora, CO
  • Florida
    • Gainesville, Florida, United States, 32608
      • North Florida/South Georgia Veterans Health System, Gainesville, FL
    • Orlando, Florida, United States, 32803
      • Orlando VA Medical Center, Orlando, FL
    • Tampa, Florida, United States, 33612
      • James A. Haley Veterans' Hospital, Tampa, FL
  • Georgia
    • Decatur, Georgia, United States, 30033
      • Atlanta VA Medical and Rehab Center, Decatur, GA
  • Illinois
    • Hines, Illinois, United States, 60141-5000
      • Edward Hines Jr. VA Hospital, Hines, IL
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • VA Ann Arbor Healthcare System, Ann Arbor, MI
    • Detroit, Michigan, United States, 48201
      • John D. Dingell VA Medical Center, Detroit, MI
  • Nevada
    • North Las Vegas, Nevada, United States, 89086
      • VA Southern Nevada Healthcare System, North Las Vegas, NV
  • New York
    • Bronx, New York, United States, 10468
      • James J. Peters VA Medical Center, Bronx, NY
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Durham VA Medical Center, Durham, NC
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Louis Stokes VA Medical Center, Cleveland, OH
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma City VA Medical Center, Oklahoma City, OK
  • Oregon
    • Portland, Oregon, United States, 97239
      • VA Portland Health Care System, Portland, OR
  • South Carolina
    • Charleston, South Carolina, United States, 29401-5799
      • Ralph H. Johnson VA Medical Center, Charleston, SC
  • Texas
    • Dallas, Texas, United States, 75216
      • VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
    • Houston, Texas, United States, 77030
      • Michael E. DeBakey VA Medical Center, Houston, TX
    • San Antonio, Texas, United States, 78229
      • South Texas Health Care System, San Antonio, TX
  • Utah
    • Salt Lake City, Utah, United States, 84148
      • VA Salt Lake City Health Care System, Salt Lake City, UT
  • Virginia
    • Richmond, Virginia, United States, 23249
      • Hunter Holmes McGuire VA Medical Center, Richmond, VA
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • William S. Middleton Memorial Veterans Hospital, Madison, WI

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Veterans must meet all of the following criteria to be eligible to participate:

1. Admitted to a participating VA clinical site with symptoms suggestive of SARS-CoV-2 infection.
2. Participant (or legally authorized representative) provides informed consent prior to initiation of any study procedures.
3. Participant (or legally authorized representative) understands and agrees to comply with planned study procedures.
4. Veteran 18 years of age at time of screening.
5. Has laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR) or antigen test, as documented by either of the following:

(1)Reverse Transcription polymerase chain reaction (RT-PCR) or antigen positive (nasopharyngeal, oropharyngeal, saliva, lower respiratory) in sample collected 72 hours prior to screening; (2)RT-PCR or antigen positive in sample collected > 72 hours but 168 hours (i.e. 7 days) prior to screening, documented inability to obtain a repeat sample (e.g. due to lack of testing supplies, limited testing capacity, results taking > 24 hours, etc.), AND progressive disease suggestive of ongoing SARS-CoV-2 infection.

6.Requiring oxygen by nasal cannula or by face-mask as a new treatment (or if previously on home oxygen, at a liter flow at least 2 Lpm greater than home prescription), but not on humidified heated high-flow nasal cannula (HHHFNC) at 15 Lpm.

7.Can be randomized within 72 hours of hospital admission. 8.Agrees not to participate in another therapeutic clinical trial for the treatment of COVID-19 or SARS-CoV-2 through Day 29 without approval from the investigator(s). Taking part in other research studies, including those unrelated to SARS-CoV-2, without first discussing it with the investigators of this study may invalidate the results of this study, as well as that of the other study.

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Respiratory failure requiring mechanical ventilation, non-invasive ventilation including continuous positive airway pressure (CPAP) (for an indication other than previously diagnosed sleep apnea and maintained on outpatient settings), or extra-corporeal membrane oxygenation or anticipated to require any of those treatments or to die within 24 hours.
2. Anticipated discharge from the hospital or transfer to another hospital that is not a study site within 72 hours.
3. History of previous transfusion reaction.
4. Previously documented serum immunoglobulin A (IgA) deficiency (<7 mg/dL)
5. Documented to have received convalescent plasma in the last 60 days.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Convalescent Plasma; The study intervention consists of intravenous administration of 200-500 mL of convalescent plasma administered in two equally divided doses, less than 12 hours apart.	Drug: Convalescent Plasma; Convalescent plasma from persons recovered from SARS-CoV-2 is being used to treat hospitalized individuals with complicated COVID-19 infection.; Other Names: COVID-19 Convalescent Plasma (CCP)
PLACEBO_COMPARATOR: Masked Saline Placebo; The study intervention consists of intravenous administration of 200-500 mL of 0.9% saline administered in two equally divided doses, less than 12 hours apart.	Other: Masked Saline Placebo; 0.9% saline solution will be used as the Masked Saline Placebo; Other Names: Normal Saline (NS)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants Developing Acute Hypoxemic Respiratory Failure or All-cause Death	Respiratory failure is defined as requiring mechanical ventilation, with or without endotracheal intubations, or extra-corporeal membrane oxygenation.	Day 1 through Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time (in Days) to Recovery	Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the Modified World Health Organization (WHO) 8-point Ordinal Scale for Clinical Improvement : 1) Ambulatory, no limitation of activity; 2) Ambulatory, limitation of activity and/or home oxygen; 3) Hospitalized Mild Disease, no oxygen therapy.	Day 1 through Day 28
Time (in Days) to Death or Respiratory Failure	Defined as the first day on which the subject died from any cause or had respiratory failure. Respiratory failure is defined by requiring mechanical ventilation, with or without endotracheal intubations, or extra-corporeal membrane oxygenation.	Day 1 through Day 28
Proportion of Patients Who Died From Any Cause, Had Respiratory Failure, or Required Humidified Heated High-flow Nasal Cannula (HHHFNC) at >= 15 Lpm	Defined as the proportion of subjects who died from any cause, had respiratory failure, or who required humidified heater high-flow cannula (HHHFNC) at >= 15 Lpm. Respiratory failure is defined by requiring mechanical ventilation, with or without endotracheal intubations, or extra-corporeal membrane oxygenation.	Day 1 through Day 28
Time (in Days) to Death, Respiratory Failure, or HHHFNC at >= 15 Lpm	Time to death or respiratory failure is defined as the first day on which the subject died from any cause, had respiratory failure (defined above), or who required HHHFNC at >= 15 Lpm.	Day 1 through Day 28
Number of Participants With 28-day All-cause Mortality	Death for Any Reason	Day 1 through Day 28
Time to an Improvement of at Least One Category Using an Ordinal Scale	Number of Days until the Modified WHO Clinical Status Improved by at Least One Category Modified WHO 8-point Ordinal Scale for Clinical Improvement. The scale is as follows: 0) No clinical or Virologic evidence of infection; 1) Ambulatory, no limitation of activity; 2) Ambulatory, limitation of activity and/or home oxygen; 3) Hospitalized Mild Disease, no oxygen therapy; 4) Hospitalized Mild Disease, oxygen by mask or nasal prong; 5a) Hospitalized Severe Disease, humidified high-flow oxygen; 5b) Hospitalized Severe Disease, non-invasive ventilation; 6) Hospitalized Severe Disease, intubation and mechanical ventilation; 7) Hospitalized Severe Disease, ventilation + additional organ support-pressors, renal replacement therapy (RRT), extracorporeal membrane oxygenation (ECMO); 8) Death. The higher the score, the worse the outcome.	Up through 28 days.
Time to an Improvement of at Least Two Categories Using an Ordinal Scale	Number of Days until the Modified WHO Clinical Status Improved by at Least Two Categories Modified WHO 8-point Ordinal Scale for Clinical Improvement. The scale is as follows: 0) No clinical or Virologic evidence of infection; 1) Ambulatory, no limitation of activity; 2) Ambulatory, limitation of activity and/or home oxygen; 3) Hospitalized Mild Disease, no oxygen therapy; 4) Hospitalized Mild Disease, oxygen by mask or nasal prong; 5a) Hospitalized Severe Disease, humidified high-flow oxygen; 5b) Hospitalized Severe Disease, non-invasive ventilation; 6) Hospitalized Severe Disease, intubation and mechanical ventilation; 7) Hospitalized Severe Disease, ventilation + additional organ support-pressors, RRT, ECMO; 8) Death. The higher the score, the worse the outcome.	Up through 28 days.
Participant's Clinical Status by Ordinal Scale	Modified WHO 8-point Ordinal Scale for Clinical Improvement. The scale is as follows: 0) No clinical or Virologic evidence of infection; 1) Ambulatory, no limitation of activity; 2) Ambulatory, limitation of activity and/or home oxygen; 3) Hospitalized Mild Disease, no oxygen therapy; 4) Hospitalized Mild Disease, oxygen by mask or nasal prong; 5a) Hospitalized Severe Disease, humidified high-flow oxygen; 5b) Hospitalized Severe Disease, non-invasive ventilation; 6) Hospitalized Severe Disease, intubation and mechanical ventilation; 7) Hospitalized Severe Disease, ventilation + additional organ support-pressors, RRT, ECMO; 8) Death. The higher the score, the worse the outcome.	Days 2, 4, 7, 11, 14, 21, and 28
Change in the Ordinal Scale From Baseline to Days 2, 4, 7, 11, 14, 21, and 28	Change in the Modified WHO Clinical Status Modified WHO 8-point Ordinal Scale for Clinical Improvement. The scale is as follows: 0) No clinical or Virologic evidence of infection; 1) Ambulatory, no limitation of activity; 2) Ambulatory, limitation of activity and/or home oxygen; 3) Hospitalized Mild Disease, no oxygen therapy; 4) Hospitalized Mild Disease, oxygen by mask or nasal prong; 5a) Hospitalized Severe Disease, humidified high-flow oxygen; 5b) Hospitalized Severe Disease, non-invasive ventilation; 6) Hospitalized Severe Disease, intubation and mechanical ventilation; 7) Hospitalized Severe Disease, ventilation + additional organ support-pressors, RRT, ECMO; 8) Death. The higher the score, the worse the outcome.	From Baseline to Days 2, 4, 7, 11, 14, 21, and 28.
Categorical Change in the Ordinal Scale From Baseline to Days 2, 4, 7, 11, 14, 21, and 28	Categorical Change in the Modified WHO 8-point Ordinal Scale for Clinical Improvement Modified WHO 8-point Ordinal Scale for Clinical Improvement. The scale is as follows: 0) No clinical or Virologic evidence of infection; 1) Ambulatory, no limitation of activity; 2) Ambulatory, limitation of activity and/or home oxygen; 3) Hospitalized Mild Disease, no oxygen therapy; 4) Hospitalized Mild Disease, oxygen by mask or nasal prong; 5a) Hospitalized Severe Disease, humidified high-flow oxygen; 5b) Hospitalized Severe Disease, non-invasive ventilation; 6) Hospitalized Severe Disease, intubation and mechanical ventilation; 7) Hospitalized Severe Disease, ventilation + additional organ support-pressors, RRT, ECMO; 8) Death. The higher the score, the worse the outcome.	From Baseline to Days 2, 4, 7, 11, 14, 21, and 28.
Time to Discharge or to a National Early Warning Score 2 (NEWS2) of <= 2 Maintained for at Least 22 Hours, Whichever Occurs First	Number of Days until Initial Hospitalization Discharge or (NEWS2 <= 2 Maintained for at Least 22 Hours) The National Early Warning Score 2 (NEWS2) score has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is based on 7 clinical parameters and ranges from 0 to 20. The NEWS2 is being used as an efficacy measure. Higher scores mean a worse outcome.	Up through 28 days.
Change in National Early Warning Score 2 (NEWS2) From Day 1 (Baseline) to Days 2, 4, 7, 11, 15, and 29	Change in NEWS2 The National Early Warning Score 2 (NEWS2) has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is based on 7 clinical parameters and ranges from 0 to 20. The NEWS2 is being used as an efficacy measure. Higher scores mean a worse outcome.	From Day 1 (baseline) to Days 2, 4, 7, 11, 15, and 29
Duration of Hospitalization	Number of Days Hospitalized During Initial Hospitalization	Day 1 through Day 28
Incidence of Discontinuation or Temporary Suspension of Study Product Administrations (for Any Reason)	Number of participants for whom study product administration was discontinued or temporarily suspended for any reason	Day 1 through Day 3

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Study Chair: Edward N. Janoff, MD, Rocky Mountain Regional VA Medical Center, Aurora, CO

Publications and helpful links

General Publications

• Miller EK, Goldberg AM, Janoff EN, Brown ST, Curtis JL, Bonomo RA, Shih MC, Gleason TC. Designing and implementing methodology for double-blind, placebo-controlled clinical trials using blood products within the Department of Veterans Affairs. Clin Trials. 2022 Apr;19(2):137-145. doi: 10.1177/17407745211069703. Epub 2022 Mar 1.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 16, 2020
• Primary Completion (ACTUAL): June 30, 2021
• Study Completion (ACTUAL): September 30, 2021

Study Registration Dates

• First Submitted: August 27, 2020
• First Submitted That Met QC Criteria: September 3, 2020
• First Posted (ACTUAL): September 4, 2020

Study Record Updates

• Last Update Posted (ACTUAL): September 23, 2022
• Last Update Submitted That Met QC Criteria: September 9, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Humans; Adults; Female; Male; Respiratory failure; COVID-19 pandemic; convalescent plasma; Treatment Outcome; SARS CoV-2; Blood Component Transfusion; Survival Analysis; Severity of Illness Index; Prospective Study; COVID-19 virus disease; COVID-19 virus infection; 2019 novel coronavirus disease; COVID-19 convalescent plasma; Pneumonia, viral / therapy
• Additional Relevant MeSH Terms: Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Coronavirus Infections
• Other Study ID Numbers: COVID19-8900-22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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