COVID-19 (VA CURES-1)

Sponsor

VA Office of Research and Development (U.S. Fed)

Overall Status

Terminated

CT.gov ID

NCT04539275

Collaborator

(none)

Enrollment

Locations

Arms

10.4

Actual Duration (Months)

3.1

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Study Design

Study Type:

Interventional

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.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 :

Nov 16, 2020

Actual Primary Completion Date :

Jun 30, 2021

Actual Study Completion Date :

Sep 30, 2021

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Proportion of participants developing acute hypoxemic respiratory failure or all-cause death [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

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 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.
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 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.
Time (in days) to death or 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 or had respiratory failure (defined above), or who required HHHFNC at 15 Lpm.
Subject 28-day all-cause mortality [Day 1 through Day 28]
Date and cause of death (if applicable)
Time to an improvement of one category using an ordinal scale [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.
Time to an improvement of two categories using an ordinal scale [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.
Participant's clinical status by ordinal scale [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.
Mean change in the 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) 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.
Time to discharge or to a National Early Warning Score (NEWS)-2 of = 2 and maintained for 24 hours, whichever occurs first [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.
Change in NEWS-2 Score 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]
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.
Duration of hospitalization [Day 1 through Day 28]
Measured in days.
Number of hospitalizations related to COVID-19 [Day 1 through Day 28]
Measured in days.
Cumulative incidence of Serious Adverse Events (SAEs) [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.
Cumulative incidence of Grade 3 and 4 clinical and/or laboratory adverse events (AEs) [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.
Incidence of discontinuation or temporary suspension of study product administrations (for any reason) [Day 1 through Day 29]
Incidence of occurrence.
Change from baseline in hemoglobin [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
Change from baseline in platelets [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
Change from baseline in creatinine [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
Change from baseline in glucose [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
Change from baseline in total bilirubin [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
Change from baseline in alanine transaminase (ALT) [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
Change from baseline in aspartate transaminase (AST) [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
Change from baseline in prothrombin time (PT) [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).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Admitted to a participating VA clinical site with symptoms suggestive of SARS-CoV-2 infection.
Participant (or legally authorized representative) provides informed consent prior to initiation of any study procedures.
Participant (or legally authorized representative) understands and agrees to comply with planned study procedures.
Veteran 18 years of age at time of screening.
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:

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.
Anticipated discharge from the hospital or transfer to another hospital that is not a study site within 72 hours.
History of previous transfusion reaction.
Previously documented serum IgA deficiency (<7 mg/dL)
Documented to have received convalescent plasma in the last 60 days.

Contacts and Locations

Locations

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