Clinical trial NCT04539275: VA CoronavirUs Research and Efficacy Studies-1
Official title: VA CoronavirUs Research and Efficacy Studies-1 (VA CURES-1)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: COVID-19
Keywords: 2019 novel coronavirus disease
COVID-19 pandemic
COVID-19 virus infection
COVID-19 virus disease
Respiratory failure
Pneumonia, viral / therapy
Blood Component Transfusion
Severity of Illness Index
Survival Analysis
Treatment Outcome
Prospective Study
Humans
Adults
Male
Female
convalescent plasma
SARS CoV-2
COVID-19 convalescent plasma
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2020-09-04
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: There are two study treatment arms: convalescent plasma versus saline. Participants will be randomized in 1:1 ratio to these two arms.
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Proportion of Participants Developing Acute Hypoxemic Respiratory Failure or All-cause Death
timeFrame: Day 1 through Day 28
Secondary outcomes:
measure: Time (in Days) to Recovery
timeFrame: Day 1 through Day 28
measure: Time (in Days) to Death or Respiratory Failure
timeFrame: Day 1 through Day 28
measure: Proportion of Patients Who Died From Any Cause, Had Respiratory Failure, or Required Humidified Heated High-flow Nasal Cannula (HHHFNC) at >= 15 Lpm
timeFrame: Day 1 through Day 28
measure: Time (in Days) to Death, Respiratory Failure, or HHHFNC at >= 15 Lpm
timeFrame: Day 1 through Day 28
measure: Number of Participants With 28-day All-cause Mortality
timeFrame: Day 1 through Day 28
measure: Time to an Improvement of at Least One Category Using an Ordinal Scale
timeFrame: Up through 28 days.
measure: Time to an Improvement of at Least Two Categories Using an Ordinal Scale
timeFrame: Up through 28 days.
measure: Participant's Clinical Status by Ordinal Scale
timeFrame: Days 2, 4, 7, 11, 14, 21, and 28
measure: Change in the Ordinal Scale From Baseline to Days 2, 4, 7, 11, 14, 21, and 28
timeFrame: From Baseline to Days 2, 4, 7, 11, 14, 21, and 28.
measure: Categorical Change in the Ordinal Scale From Baseline to Days 2, 4, 7, 11, 14, 21, and 28
timeFrame: From Baseline to Days 2, 4, 7, 11, 14, 21, and 28.
measure: Time to Discharge or to a National Early Warning Score 2 (NEWS2) of <= 2 Maintained for at Least 22 Hours, Whichever Occurs First
timeFrame: Up through 28 days.
measure: Change in National Early Warning Score 2 (NEWS2) From Day 1 (Baseline) to Days 2, 4, 7, 11, 15, and 29
timeFrame: From Day 1 (baseline) to Days 2, 4, 7, 11, 15, and 29
measure: Duration of Hospitalization
timeFrame: Day 1 through Day 28
measure: Incidence of Discontinuation or Temporary Suspension of Study Product Administrations (for Any Reason)
timeFrame: Day 1 through Day 3
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Birmingham VA Medical Center, Birmingham, AL
state: Alabama
city: Phoenix
country: United States
facility: Phoenix VA Health Care System, Phoenix, AZ
state: Arizona
city: Aurora
country: United States
facility: Rocky Mountain Regional VA Medical Center, Aurora, CO
state: Colorado
city: Gainesville
country: United States
facility: North Florida/South Georgia Veterans Health System, Gainesville, FL
state: Florida
city: Orlando
country: United States
facility: Orlando VA Medical Center, Orlando, FL
state: Florida
city: Tampa
country: United States
facility: James A. Haley Veterans' Hospital, Tampa, FL
state: Florida
city: Decatur
country: United States
facility: Atlanta VA Medical and Rehab Center, Decatur, GA
state: Georgia
city: Hines
country: United States
facility: Edward Hines Jr. VA Hospital, Hines, IL
state: Illinois
city: Ann Arbor
country: United States
facility: VA Ann Arbor Healthcare System, Ann Arbor, MI
state: Michigan
city: Detroit
country: United States
facility: John D. Dingell VA Medical Center, Detroit, MI
state: Michigan
city: North Las Vegas
country: United States
facility: VA Southern Nevada Healthcare System, North Las Vegas, NV
state: Nevada
city: Bronx
country: United States
facility: James J. Peters VA Medical Center, Bronx, NY
state: New York
city: Durham
country: United States
facility: Durham VA Medical Center, Durham, NC
state: North Carolina
city: Cleveland
country: United States
facility: Louis Stokes VA Medical Center, Cleveland, OH
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma City VA Medical Center, Oklahoma City, OK
state: Oklahoma
city: Portland
country: United States
facility: VA Portland Health Care System, Portland, OR
state: Oregon
city: Charleston
country: United States
facility: Ralph H. Johnson VA Medical Center, Charleston, SC
state: South Carolina
city: Dallas
country: United States
facility: VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
state: Texas
city: Houston
country: United States
facility: Michael E. DeBakey VA Medical Center, Houston, TX
state: Texas
city: San Antonio
country: United States
facility: South Texas Health Care System, San Antonio, TX
state: Texas
city: Salt Lake City
country: United States
facility: VA Salt Lake City Health Care System, Salt Lake City, UT
state: Utah
city: Richmond
country: United States
facility: Hunter Holmes McGuire VA Medical Center, Richmond, VA
state: Virginia
city: Madison
country: United States
facility: William S. Middleton Memorial Veterans Hospital, Madison, WI
state: Wisconsin
city: San Juan
country: Puerto Rico
facility: VA Caribbean Healthcare System, San Juan, PR
Study officials:
affiliation: Rocky Mountain Regional VA Medical Center, Aurora, CO
name: Edward N. Janoff, MD
role: STUDY_CHAIR
References:
citation: 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.