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COVID-19 (VA CURES-1) (VA CURES-1)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04539275
Recruitment Status : Completed
First Posted : September 4, 2020
Last Update Posted : October 14, 2021
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

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.

Condition or disease Intervention/treatment Phase
COVID-19 Drug: Convalescent Plasma Other: Masked Saline Placebo Phase 3

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 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 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, CA unless otherwise specified. The biospecimens will be accessible for future research with an approved Sample Use Agreement. The VA 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 75 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:

The participants, site investigators, clinical prescribers, site coordinators, and most other individuals involved in this study will be blinded to the treatment assignment.

Furthermore, the blind will not routinely be broken in order to select post-study, pharmacologic treatment for SARS-CoV-2 infection administered by clinical healthcare providers.

Primary Purpose: Treatment
Official Title: VA CoronavirUs Research and Efficacy Studies-1 (VA CURES-1)
Actual Study Start Date : November 16, 2020
Actual Primary Completion Date : June 30, 2021
Actual Study Completion Date : September 30, 2021

Arm Intervention/treatment
Experimental: Convalescent Plasma
The study intervention consists of intravenous administration of 200-500mL 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.

Placebo Comparator: Masked Saline Placebo
The study intervention consists of intravenous administration of 200-500mL 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




Primary Outcome Measures :
  1. Proportion of participants developing acute hypoxemic respiratory failure or all-cause death [ Time Frame: Day 1 through Day 28 ]
    Respiratory failure is defined by requiring mechanical ventilation, with or without endotracheal intubations, or extra-corporeal membrane oxygenation.


Secondary Outcome Measures :
  1. Time (in days) to recovery [ Time Frame: 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 ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care.

  2. Time (in days) to death or respiratory failure [ Time Frame: 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.

  3. Proportion of patients who died from any cause, had respiratory failure, or required humidified heated high-flow nasal cannula (HHHFNC) at 15 Lpm [ Time Frame: Day 1 through Day 28 ]
    Defined as the proportion of subjects who died from any cause or had respiratory failure, or who required humidified heater high-flow cannula (HHHFNC). Respiratory failure is defined by requiring mechanical ventilation, with or without endotracheal intubations, or extra-corporeal membrane oxygenation.

  4. Time (in days) to death or respiratory failure or HHHFNC at 15 Lpm [ Time Frame: 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 or had respiratory failure (defined above), or who required HHHFNC at 15 Lpm.

  5. Subject 28-day all-cause mortality [ Time Frame: Day 1 through Day 28 ]
    Date and cause of death (if applicable)

  6. Time to an improvement of one category using an ordinal scale [ Time Frame: Up through 28 days. ]
    Modified WHO 8-point Ordinal Scale for Clinical Improvement. The scale is as follows: 0) No clinical or Virologic evidence of infection; 1) No limitation of activity; 2) Limitation of activity and/or home oxygen; 3) Hospitalized, no oxygen therapy; 4) Oxygen by mask or nasal prong; 5a) Humidified high-flow oxygen; 5b) Non-invasive ventilation; 6) Intubation and mechanical Ventilation; 7) Ventilation + additional organ support-pressors, RRT, ECMO; 8) Death. The higher the score, the worse the outcome.

  7. Time to an improvement of two categories using an ordinal scale [ Time Frame: Up through 28 days. ]
    Modified WHO 8-point Ordinal Scale for Clinical Improvement. The scale is as follows: 0) No clinical or Virologic evidence of infection; 1) No limitation of activity; 2) Limitation of activity and/or home oxygen; 3) Hospitalized, no oxygen therapy; 4) Oxygen by mask or nasal prong; 5a) Humidified high-flow oxygen; 5b) Non-invasive ventilation; 6) Intubation and mechanical Ventilation; 7) Ventilation + additional organ support-pressors, RRT, ECMO; 8) Death. The higher the score, the worse the outcome.

  8. Participant's clinical status by ordinal scale [ Time Frame: Up through 28 days. ]
    Modified WHO 8-point Ordinal Scale for Clinical Improvement. The scale is as follows: 0) No clinical or Virologic evidence of infection; 1) No limitation of activity; 2) Limitation of activity and/or home oxygen; 3) Hospitalized, no oxygen therapy; 4) Oxygen by mask or nasal prong; 5a) Humidified high-flow oxygen; 5b) Non-invasive ventilation; 6) Intubation and mechanical Ventilation; 7) Ventilation + additional organ support-pressors, RRT, ECMO; 8) Death. The higher the score, the worse the outcome.

  9. Mean change in the ordinal scale [ Time Frame: 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) No limitation of activity; 2) Limitation of activity and/or home oxygen; 3) Hospitalized, no oxygen therapy; 4) Oxygen by mask or nasal prong; 5a) Humidified high-flow oxygen; 5b) Non-invasive ventilation; 6) Intubation and mechanical Ventilation; 7) Ventilation + additional organ support-pressors, RRT, ECMO; 8) Death. The higher the score, the worse the outcome.

  10. Time to discharge or to a National Early Warning Score (NEWS)-2 of = 2 and maintained for 24 hours, whichever occurs first [ Time Frame: Up through 28 days. ]
    The NEWS2 score has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is based on 7 clinical parameters. The NEW Score-2 is being used as an efficacy measure.

  11. Change in NEWS-2 Score from Day 1 (baseline) to Days 2, 4, 7, 11, 15, and 29 [ Time Frame: From Day 1 (baseline) to Days 2, 4, 7, 11, 15, and 29 ]
    The NEWS2 score has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is based on 7 clinical parameters. The NEW Score-2 is being used as an efficacy measure.

  12. Duration of hospitalization [ Time Frame: Day 1 through Day 28 ]
    Measured in days.

  13. Number of hospitalizations related to COVID-19 [ Time Frame: Day 1 through Day 28 ]
    Measured in days.

  14. Cumulative incidence of Serious Adverse Events (SAEs) [ Time Frame: Day 1 through Day 29 ]
    An SAE is defined as an AE or suspected adverse reaction is considered serious if, in the view of either the investigator or the sponsor, it results in death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect.

  15. Cumulative incidence of Grade 3 and 4 clinical and/or laboratory adverse events (AEs) [ Time Frame: Day 1 through Day 29 ]
    Grade 3 AEs are defined as events that interrupt usual activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention. Severe events are usually incapacitating. Grade 4 AEs are defined as events that are potentially life threatening.

  16. Incidence of discontinuation or temporary suspension of study product administrations (for any reason) [ Time Frame: Day 1 through Day 29 ]
    Incidence of occurrence.

  17. Change from baseline in hemoglobin [ Time Frame: Day 1 to Days 2, 4, and 7 (while hospitalized); and Days 15 and 29 (if attends in-person visit or still hospitalized). ]
    g/dL

  18. Change from baseline in platelets [ Time Frame: Day 1 to Days 2, 4, and 7 (while hospitalized); and Days 15 and 29 (if attends in-person visit or still hospitalized). ]
    K/mcL

  19. Change from baseline in creatinine [ Time Frame: Day 1 to Days 2, 4, and 7 (while hospitalized); and Days 15 and 29 (if attends in-person visit or still hospitalized). ]
    mm/L

  20. Change from baseline in glucose [ Time Frame: Day 1 to Days 2, 4, and 7 (while hospitalized); and Days 15 and 29 (if attends in-person visit or still hospitalized). ]
    mg/dL

  21. Change from baseline in total bilirubin [ Time Frame: Day 1 to Days 2, 4, and 7 (while hospitalized); and Days 15 and 29 (if attends in-person visit or still hospitalized). ]
    mg/dL

  22. Change from baseline in alanine transaminase (ALT) [ Time Frame: Day 1 to Days 2, 4, and 7 (while hospitalized); and Days 15 and 29 (if attends in-person visit or still hospitalized). ]
    U/L

  23. Change from baseline in aspartate transaminase (AST) [ Time Frame: Day 1 to Days 2, 4, and 7 (while hospitalized); and Days 15 and 29 (if attends in-person visit or still hospitalized). ]
    U/L

  24. Change from baseline in prothrombin time (PT) [ Time Frame: Day 1 to Days 2, 4, and 7 (while hospitalized); and Days 15 and 29 (if attends in-person visit or still hospitalized). ]
    PT reported as international normalized ratio (INR).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)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 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 IgA deficiency (<7 mg/dL)
  5. Documented to have received convalescent plasma in the last 60 days.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04539275


Locations
Show Show 24 study locations
Sponsors and Collaborators
VA Office of Research and Development
Investigators
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Study Chair: Edward N. Janoff, MD Rocky Mountain Regional VA Medical Center, Aurora, CO
  Study Documents (Full-Text)

Documents provided by VA Office of Research and Development:
Informed Consent Form  [PDF] February 18, 2021

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Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT04539275    
Other Study ID Numbers: COVID19-8900-22
First Posted: September 4, 2020    Key Record Dates
Last Update Posted: October 14, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by VA Office of Research and Development:
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
Additional relevant MeSH terms:
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COVID-19
Respiratory Tract Infections
Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases