VA CoronavirUs Research and Efficacy Studies-1

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.

• Convalescent Plasma (Drug), also known as COVID-19 Convalescent Plasma (CCP): Convalescent plasma from persons recovered from SARS-CoV-2 is being used to treat hospitalized individuals with complicated COVID-19 infection.
• Masked Saline Placebo (Other), also known as Normal Saline (NS): 0.9% saline solution will be used as the Masked Saline Placebo

Primary outcomes

• Proportion of Participants Developing Acute Hypoxemic Respiratory Failure or All-cause Death [Day 1 through Day 28]: Respiratory failure is defined as requiring mechanical ventilation, with or without endotracheal intubations, or extra-corporeal membrane oxygenation.

Secondary outcomes

• Time (in Days) to Recovery [Day 1 through Day 28]: 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.
• Time (in Days) to Death or Respiratory Failure [Day 1 through Day 28]: 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.
• Proportion of Patients Who Died From Any Cause, Had Respiratory Failure, or Required Humidified Heated High-flow Nasal Cannula (HHHFNC) at >= 15 Lpm [Day 1 through Day 28]: 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.
• Time (in Days) to Death, Respiratory Failure, or HHHFNC at >= 15 Lpm [Day 1 through Day 28]: 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.
• Number of Participants With 28-day All-cause Mortality [Day 1 through Day 28]: Death for Any Reason
• Time to an Improvement of at Least One Category Using an Ordinal Scale [Up through 28 days.]: 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.
• Time to an Improvement of at Least Two Categories Using an Ordinal Scale [Up through 28 days.]: 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.
• Participant's Clinical Status by Ordinal Scale [Days 2, 4, 7, 11, 14, 21, and 28]: 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.
• Change in the Ordinal Scale From Baseline to Days 2, 4, 7, 11, 14, 21, and 28 [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.
• Categorical Change in the Ordinal Scale From Baseline to Days 2, 4, 7, 11, 14, 21, and 28 [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.
• Time to Discharge or to a National Early Warning Score 2 (NEWS2) of <= 2 Maintained for at Least 22 Hours, Whichever Occurs First [Up through 28 days.]: 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.
• Change in National Early Warning Score 2 (NEWS2) From Day 1 (Baseline) to Days 2, 4, 7, 11, 15, and 29 [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.
• Duration of Hospitalization [Day 1 through Day 28]: Number of Days Hospitalized During Initial Hospitalization
• Incidence of Discontinuation or Temporary Suspension of Study Product Administrations (for Any Reason) [Day 1 through Day 3]: Number of participants for whom study product administration was discontinued or temporarily suspended for any reason

Sex: All, ages: 18 Years to any

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.

Participant flow

Outcome results

• Proportion of Participants Developing Acute Hypoxemic Respiratory Failure or All-cause Death (Primary), Count of participants, Participants: Convalescent Plasma 3; Masked Saline Placebo 4 (p 1.00)
• Time (in Days) to Recovery (Secondary), Median, Days: Convalescent Plasma 6 (4 to 9); Masked Saline Placebo 6 (5 to 12.5) (p 0.749)
• Time (in Days) to Death or Respiratory Failure (Secondary), Median, days: Convalescent Plasma NA (NA to NA); Masked Saline Placebo NA (NA to NA) (p 0.943)
• Proportion of Patients Who Died From Any Cause, Had Respiratory Failure, or Required Humidified Heated High-flow Nasal Cannula (HHHFNC) at >= 15 Lpm (Secondary), Count of participants, Participants: Convalescent Plasma 4; Masked Saline Placebo 8 (p 0.4014)
• Time (in Days) to Death, Respiratory Failure, or HHHFNC at >= 15 Lpm (Secondary), Median, days: Convalescent Plasma NA (NA to NA); Masked Saline Placebo NA (NA to NA) (p 0.3762)
• Number of Participants With 28-day All-cause Mortality (Secondary), Count of participants, Participants: Convalescent Plasma 2; Masked Saline Placebo 4 (p 0.6867)
• Time to an Improvement of at Least One Category Using an Ordinal Scale (Secondary), Median, days: Convalescent Plasma 6 (4 to 9); Masked Saline Placebo 6 (5 to 12.5) (p 0.6494)
• Time to an Improvement of at Least Two Categories Using an Ordinal Scale (Secondary), Median, days: Convalescent Plasma 7 (5 to 13); Masked Saline Placebo 7 (5 to 16) (p 0.9338)
• Participant's Clinical Status by Ordinal Scale (Secondary), Count of participants, Participants: Convalescent Plasma 0; Masked Saline Placebo 0
• Change in the Ordinal Scale From Baseline to Days 2, 4, 7, 11, 14, 21, and 28 (Secondary), Median, units on a scale: Convalescent Plasma 0 (-1 to 1); Masked Saline Placebo 0 (-1 to 3)
• Categorical Change in the Ordinal Scale From Baseline to Days 2, 4, 7, 11, 14, 21, and 28 (Secondary), Count of participants, Participants: Convalescent Plasma 0; Masked Saline Placebo 0
• Time to Discharge or to a National Early Warning Score 2 (NEWS2) of <= 2 Maintained for at Least 22 Hours, Whichever Occurs First (Secondary), Median, days: Convalescent Plasma 4 (3 to 7); Masked Saline Placebo 4.5 (3 to 10.5) (p 0.5682)
• Change in National Early Warning Score 2 (NEWS2) From Day 1 (Baseline) to Days 2, 4, 7, 11, 15, and 29 (Secondary), Median, score on a scale: Convalescent Plasma 0 (-0.5 to 1); Masked Saline Placebo 0 (-1 to 1)
• Duration of Hospitalization (Secondary), Median, days: Convalescent Plasma 5.5 (4 to 8.5); Masked Saline Placebo 6 (4 to 10.5) (p 0.8642)
• Incidence of Discontinuation or Temporary Suspension of Study Product Administrations (for Any Reason) (Secondary), Count of participants, Participants: Convalescent Plasma 0; Masked Saline Placebo 0

Adverse events

Time frame: 28 days

Serious adverse events by term

Other adverse events by term

• Results publication: Janoff EN, Shih MC, Donskey C, Belitskaya-Levy I, Brau N, Rodriguez-Barradas MC, Chan E, Zimmerman P, Miller EK, Vaughan LB, Daniel Markley J, Goldberg AM, Sriram P, Anzueto A, Uyeda L, Zehm L, Wills A, Hutchinson C, Jones L, Peterson D, Ringer RJ, Dumont L, Gleason T, Bonomo RA, Curtis JL, Brown ST; CURES-1 Trials Consortium. Impact of High-Titer Convalescent Plasma on Clinical and Virologic Outcomes Among Veterans Hospitalized With SARS-CoV-2 Infection: VA CoronavirUs Research and Efficacy Studies-1 (VA CURES-1). J Med Virol. 2025 May;97(5):e70349. doi: 10.1002/jmv.70349. PMID 40400480
• Results publication: Janoff EN, Brown ST, Belitskaya-Levy I, Curtis JL, Bonomo RA, Miller EK, Goldberg AM, Zehm L, Wills A, Hutchinson C, Dumont LJ, Gleason T, Shih MC; ADD Caitlin MS in CCTC website. Design of VA CoronavirUs Research and Efficacy Studies-1 (VA CURES-1): A double-blind, randomized placebo-controlled trial of COVID-19 convalescent plasma in hospitalized patients with early respiratory compromise. Contemp Clin Trials Commun. 2023 Jul 17;35:101190. doi: 10.1016/j.conctc.2023.101190. eCollection 2023 Oct. PMID 37560085
• Results publication: 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. PMID 35229691

• Study Protocol and Statistical Analysis Plan (PDF, 2021-09-22)
• Informed Consent Form (PDF, 2021-02-18)

• Edward N. Janoff, MD, Study chair, Rocky Mountain Regional VA Medical Center, Aurora, CO