Covid19
Conditions
Brief summary
The overarching goal of this project is to confirm or refute the role of passive immunization as a safe and efficacious therapy in preventing the progression from mild to severe/critical COVID-19 illness and to understand the immunologic kinetics of anti-SARS-CoV-2 antibodies after passive immunization.The primary objective is to determine the efficacy and safety of a single dose of convalescent plasma (CP) for preventing the progression from mild to severe COVID-19 illness. The secondary objective is to characterize the immunologic response to CP administration. This study will enroll adults presenting to the emergency department (ED) with mild, symptomatic, laboratory-confirmed COVID-19 illness, who are at high risk for progression to severe/critical illness, but who are clinically stable for outpatient management at randomization.
Interventions
BIOLOGICALConvalescent Plasma
SARS-CoV-2 convalescent plasma with neutralizing SARS-CoV2 antibodies titers of ≥1:160 administered via intravenous (IV) infusion.
BIOLOGICALSaline
Saline with multivitamin administered via intravenous (IV) infusion..
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Strategies to Innovate EmeRgENcy Care Clinical Trials Network
University of Pittsburgh
Medical University of South Carolina
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* One or more symptoms of COVID-19 illness and laboratory-confirmed SARS-CoV-2 infection * Has at least one study defined risk factor for severe COVID-19 illness * Clinical team deems stable for outpatient management without supplemental oxygen * CP available at the site at the time of enrollment * Duration of symptoms ≤ 7 days at ED presentation * Informed consent from subject
Exclusion criteria
* Age less than 18 years * Prisoner or ward of the state * Presumed unable to complete follow-up assessments * Prior adverse reaction(s) from blood product transfusion * Receipt of any blood product within the past 120 days * Treating clinical team unwilling to administer 300 ml fluid * Enrollment in another interventional trial for COVID-19 illness
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Disease Progression (Intention-to-treat Population) | 15 days | Disease progression defined as death or hospital admission or seeking emergency or urgent care within 15 days of randomization. |
| Number of Patients With Disease Progression (Per-protocol Population) | 15 days | Disease progression defined as death or hospital admission or seeking emergency or urgent care within 15 days of randomization. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Worst Severity Rating on the WHO COVID Ordinal Scale for Clinical Improvement During the 30 Days Following Randomization | 30 days | This scale was developed by a special World Health Organization (WHO) committee for quantifying COVID-19 illness severity. * 1 = Not hospitalized without limitation in activity (no symptoms) * 2 = Not hospitalized with limitation in activity (continued symptoms) * 3 = Hospitalized not on supplemental oxygen * 4 = Hospitalized on supplemental oxygen by mask or nasal prongs * 5 = Hospitalized on non-invasive ventilation or high flow nasal cannula * 6 = Hospitalized, intubated and mechanically ventilated * 7 = Hospitalized, intubated, mechanically ventilated and requiring additional organ support (pressors, renal replacement therapy) * 8 = Death |
| Number of Patients With Worsening of Symptoms at Day 15 as a Measure of Time to Disease Progression | 15 days | Assessed on the COVID Outpatient Ordinal Outcome Scale censored at 15 days after randomization. Scale provides more granular detail for outpatients than the WHO scale (adapted from Harrell and Lindsell, 2020). Worsening of symptoms is defined as any subject admitted to the hospital (level 1), seen in the emergency room (level 2), a patient who reports increased symptoms of 2 levels on the scale over a 24 hour period, or a patient who reports increased symptoms of 1 level observed for a 48 hour period. COVID Outpatient Ordinal Outcomes Scale * 1 = patient requires care in the hospital * 2 = patient requires care in the emergency department or urgent care * 3 = patient at home with symptoms rated as moderate (defined as fever, shortness of breath, abdominal pain) * 4 = patient at home with symptoms rated as mild (defined as afebrile, constitutional symptoms (flu-like illness) without shortness * 5 = patient in their usual state of health |
| Number of Hospital-free Days During the 30 Days Following Randomization | 30 days | — |
| All-cause Mortality | Assessed at 30 days | — |
Countries
United States
Participant flow
Recruitment details
Patients were enrolled at 48 hospital emergency departments in 21 states.
Participants by arm
| Arm | Count |
|---|---|
| Convalescent Plasma Participants receive 1 unit of convalescent plasma (with neutralizing SARS-CoV2 antibodies) administered via intravenous (IV) infusion. | 257 |
| Placebo Participants receive 1 unit of saline with multivitamin administered via intravenous (IV) infusion. | 254 |
| Total | 511 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 5 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | Convalescent Plasma |
|---|---|---|---|
| Age, Continuous | 54 years | 54 years | 54 years |
| Eligibility risk factor Active cancer | 2 Participants | 4 Participants | 2 Participants |
| Eligibility risk factor Age .50 yr | 155 Participants | 310 Participants | 155 Participants |
| Eligibility risk factor Body-mass index ≥30 | 150 Participants | 302 Participants | 152 Participants |
| Eligibility risk factor Chronic kidney disease | 12 Participants | 28 Participants | 16 Participants |
| Eligibility risk factor Chronic lung disease | 15 Participants | 31 Participants | 16 Participants |
| Eligibility risk factor Congestive heart disease | 11 Participants | 20 Participants | 9 Participants |
| Eligibility risk factor COPD or asthma | 68 Participants | 124 Participants | 56 Participants |
| Eligibility risk factor Coronary artery disease | 23 Participants | 51 Participants | 28 Participants |
| Eligibility risk factor Currently pregnant | 3 Participants | 6 Participants | 3 Participants |
| Eligibility risk factor Current or former tobacco use | 71 Participants | 152 Participants | 81 Participants |
| Eligibility risk factor Diabetes mellitus | 66 Participants | 142 Participants | 76 Participants |
| Eligibility risk factor Hypertension | 111 Participants | 216 Participants | 105 Participants |
| Eligibility risk factor Immunosuppression | 17 Participants | 50 Participants | 33 Participants |
| Eligibility risk factor Organ transplant recipient | 0 Participants | 5 Participants | 5 Participants |
| Eligibility risk factor Sickle-cell disease | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 73 Participants | 156 Participants | 83 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 179 Participants | 349 Participants | 170 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 6 Participants | 4 Participants |
| Interval between randomization and infusion | 69 minutes | 81 minutes | 92 minutes |
| Number of eligibility risk factors 1 | 66 Participants | 117 Participants | 51 Participants |
| Number of eligibility risk factors 3 | 65 Participants | 130 Participants | 65 Participants |
| Number of eligibility risk factors ≥3 | 123 Participants | 264 Participants | 141 Participants |
| Other coexisting illness Current or former alcohol abuse | 16 Participants | 36 Participants | 20 Participants |
| Other coexisting illness Current or former drug abuse | 17 Participants | 35 Participants | 18 Participants |
| Other coexisting illness Liver disease | 6 Participants | 18 Participants | 12 Participants |
| Other coexisting illness Other hematologic disorder | 8 Participants | 17 Participants | 9 Participants |
| Other coexisting illness Thromboembolic disorder | 10 Participants | 25 Participants | 15 Participants |
| Race/Ethnicity, Customized Asian | 10 Participants | 18 Participants | 8 Participants |
| Race/Ethnicity, Customized Black | 54 Participants | 103 Participants | 49 Participants |
| Race/Ethnicity, Customized Other | 25 Participants | 53 Participants | 28 Participants |
| Race/Ethnicity, Customized White | 165 Participants | 337 Participants | 172 Participants |
| Region of Enrollment United States | 254 Participants | 511 Participants | 257 Participants |
| Sex: Female, Male Female | 139 Participants | 274 Participants | 135 Participants |
| Sex: Female, Male Male | 115 Participants | 237 Participants | 122 Participants |
| Symptom duration before randomization | 3 days | 4 days | 4 days |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 257 | 1 / 254 |
| other Total, other adverse events | 51 / 257 | 35 / 254 |
| serious Total, serious adverse events | 59 / 257 | 64 / 254 |
Outcome results
Primary
Number of Patients With Disease Progression (Intention-to-treat Population)
Disease progression defined as death or hospital admission or seeking emergency or urgent care within 15 days of randomization.
Time frame: 15 days
Population: Intention-to-treat population included all randomized participants.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Convalescent Plasma | Number of Patients With Disease Progression (Intention-to-treat Population) | Patients with a disease-progression event | 77 Participants |
| Convalescent Plasma | Number of Patients With Disease Progression (Intention-to-treat Population) | Hospital admission for any reason | 51 Participants |
| Convalescent Plasma | Number of Patients With Disease Progression (Intention-to-treat Population) | Seeking emergency or urgent care | 25 Participants |
| Convalescent Plasma | Number of Patients With Disease Progression (Intention-to-treat Population) | Death without hospitalization | 1 Participants |
| Placebo | Number of Patients With Disease Progression (Intention-to-treat Population) | Death without hospitalization | 0 Participants |
| Placebo | Number of Patients With Disease Progression (Intention-to-treat Population) | Patients with a disease-progression event | 81 Participants |
| Placebo | Number of Patients With Disease Progression (Intention-to-treat Population) | Seeking emergency or urgent care | 25 Participants |
| Placebo | Number of Patients With Disease Progression (Intention-to-treat Population) | Hospital admission for any reason | 56 Participants |
Comparison: Analysis is of patients with a disease-progression event. The trial required a sample size of 900 patients to detect an absolute between-group difference of 10 percentage points (the minimum difference that we considered to be clinically important) with a power of 85%.
Comparison: Analysis is of patients with a disease-progression event.95% CI: [-5.9, 10.4]
Primary
Number of Patients With Disease Progression (Per-protocol Population)
Disease progression defined as death or hospital admission or seeking emergency or urgent care within 15 days of randomization.
Time frame: 15 days
Population: Per-protocol population included all the patients who had undergone randomization after the exclusion of those who did not receive the assigned trial product, had an identified eligibility violation, or had a disease-progression event before the initiation of treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Convalescent Plasma | Number of Patients With Disease Progression (Per-protocol Population) | Patients with a disease-progression event | 71 Participants |
| Convalescent Plasma | Number of Patients With Disease Progression (Per-protocol Population) | Seeking emergency or urgent care | 24 Participants |
| Convalescent Plasma | Number of Patients With Disease Progression (Per-protocol Population) | Hospital admission for any reason | 47 Participants |
| Convalescent Plasma | Number of Patients With Disease Progression (Per-protocol Population) | Death without hospitalization | 0 Participants |
| Placebo | Number of Patients With Disease Progression (Per-protocol Population) | Death without hospitalization | 0 Participants |
| Placebo | Number of Patients With Disease Progression (Per-protocol Population) | Patients with a disease-progression event | 80 Participants |
| Placebo | Number of Patients With Disease Progression (Per-protocol Population) | Hospital admission for any reason | 55 Participants |
| Placebo | Number of Patients With Disease Progression (Per-protocol Population) | Seeking emergency or urgent care | 25 Participants |
Comparison: Analysis is of patients with a disease-progression event.
Secondary
All-cause Mortality
Time frame: Assessed at 30 days
Population: Intention-to-treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Convalescent Plasma | All-cause Mortality | 5 Participants |
| Placebo | All-cause Mortality | 1 Participants |
Secondary
Number of Hospital-free Days During the 30 Days Following Randomization
Time frame: 30 days
Population: Intention-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Convalescent Plasma | Number of Hospital-free Days During the 30 Days Following Randomization | 28.3 days | Standard Deviation 4.9 |
| Placebo | Number of Hospital-free Days During the 30 Days Following Randomization | 28.6 days | Standard Deviation 3.6 |
95% CI: [-0.4, 1.1]
Secondary
Number of Patients With Worsening of Symptoms at Day 15 as a Measure of Time to Disease Progression
Assessed on the COVID Outpatient Ordinal Outcome Scale censored at 15 days after randomization. Scale provides more granular detail for outpatients than the WHO scale (adapted from Harrell and Lindsell, 2020). Worsening of symptoms is defined as any subject admitted to the hospital (level 1), seen in the emergency room (level 2), a patient who reports increased symptoms of 2 levels on the scale over a 24 hour period, or a patient who reports increased symptoms of 1 level observed for a 48 hour period. COVID Outpatient Ordinal Outcomes Scale * 1 = patient requires care in the hospital * 2 = patient requires care in the emergency department or urgent care * 3 = patient at home with symptoms rated as moderate (defined as fever, shortness of breath, abdominal pain) * 4 = patient at home with symptoms rated as mild (defined as afebrile, constitutional symptoms (flu-like illness) without shortness * 5 = patient in their usual state of health
Time frame: 15 days
Population: Intention-to-treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Convalescent Plasma | Number of Patients With Worsening of Symptoms at Day 15 as a Measure of Time to Disease Progression | 107 Participants |
| Placebo | Number of Patients With Worsening of Symptoms at Day 15 as a Measure of Time to Disease Progression | 116 Participants |
95% CI: [0.69, 1.17]
Secondary
Worst Severity Rating on the WHO COVID Ordinal Scale for Clinical Improvement During the 30 Days Following Randomization
This scale was developed by a special World Health Organization (WHO) committee for quantifying COVID-19 illness severity. * 1 = Not hospitalized without limitation in activity (no symptoms) * 2 = Not hospitalized with limitation in activity (continued symptoms) * 3 = Hospitalized not on supplemental oxygen * 4 = Hospitalized on supplemental oxygen by mask or nasal prongs * 5 = Hospitalized on non-invasive ventilation or high flow nasal cannula * 6 = Hospitalized, intubated and mechanically ventilated * 7 = Hospitalized, intubated, mechanically ventilated and requiring additional organ support (pressors, renal replacement therapy) * 8 = Death
Time frame: 30 days
Population: Participants with available data are included in the analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Convalescent Plasma | Worst Severity Rating on the WHO COVID Ordinal Scale for Clinical Improvement During the 30 Days Following Randomization | Severity rating 1 | 55 Participants |
| Convalescent Plasma | Worst Severity Rating on the WHO COVID Ordinal Scale for Clinical Improvement During the 30 Days Following Randomization | Severity rating 2 | 141 Participants |
| Convalescent Plasma | Worst Severity Rating on the WHO COVID Ordinal Scale for Clinical Improvement During the 30 Days Following Randomization | Severity rating 3 | 12 Participants |
| Convalescent Plasma | Worst Severity Rating on the WHO COVID Ordinal Scale for Clinical Improvement During the 30 Days Following Randomization | Severity rating 4 | 28 Participants |
| Convalescent Plasma | Worst Severity Rating on the WHO COVID Ordinal Scale for Clinical Improvement During the 30 Days Following Randomization | Severity rating 5 | 6 Participants |
| Convalescent Plasma | Worst Severity Rating on the WHO COVID Ordinal Scale for Clinical Improvement During the 30 Days Following Randomization | Severity rating 6 | 1 Participants |
| Convalescent Plasma | Worst Severity Rating on the WHO COVID Ordinal Scale for Clinical Improvement During the 30 Days Following Randomization | Severity rating 7 | 2 Participants |
| Convalescent Plasma | Worst Severity Rating on the WHO COVID Ordinal Scale for Clinical Improvement During the 30 Days Following Randomization | Severity rating 8 | 5 Participants |
| Placebo | Worst Severity Rating on the WHO COVID Ordinal Scale for Clinical Improvement During the 30 Days Following Randomization | Severity rating 8 | 1 Participants |
| Placebo | Worst Severity Rating on the WHO COVID Ordinal Scale for Clinical Improvement During the 30 Days Following Randomization | Severity rating 1 | 55 Participants |
| Placebo | Worst Severity Rating on the WHO COVID Ordinal Scale for Clinical Improvement During the 30 Days Following Randomization | Severity rating 5 | 5 Participants |
| Placebo | Worst Severity Rating on the WHO COVID Ordinal Scale for Clinical Improvement During the 30 Days Following Randomization | Severity rating 2 | 133 Participants |
| Placebo | Worst Severity Rating on the WHO COVID Ordinal Scale for Clinical Improvement During the 30 Days Following Randomization | Severity rating 7 | 2 Participants |
| Placebo | Worst Severity Rating on the WHO COVID Ordinal Scale for Clinical Improvement During the 30 Days Following Randomization | Severity rating 3 | 17 Participants |
| Placebo | Worst Severity Rating on the WHO COVID Ordinal Scale for Clinical Improvement During the 30 Days Following Randomization | Severity rating 6 | 0 Participants |
| Placebo | Worst Severity Rating on the WHO COVID Ordinal Scale for Clinical Improvement During the 30 Days Following Randomization | Severity rating 4 | 35 Participants |