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CompletedNCT04355767C3POUpdated Oct 19, 2021Results posted

Convalescent Plasma in Outpatients With COVID-19

A Phase 3 interventional study of Convalescent Plasma and Saline in Covid19, sponsored by Stanford University. Completed at 53 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2021-10-19.

Sponsored by Stanford University · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
511
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study 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.

02

Conditions studied

  • Covid19

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03

In context

COVID-19

7,640 studies on the registry are indexed under COVID-19; 488 are open to participants now.

This study's enrollment of 511 is above the median of 100 across 4,099 interventional studies indexed under COVID-19.

Browse COVID-19 studies →

Lead sponsor

Stanford University is the lead sponsor of 2,117 studies on the registry; 425 are open to participants now.

Of its 259 completed or terminated interventional studies of FDA-regulated products, 197 (76%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts 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

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
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Double (Participant, Outcomes assessor)
Enrollment
511 participants (actual)

Study arms

  • Experimental
    Convalescent Plasma

    Participants receive 1 unit of convalescent plasma.

    Biological: Convalescent Plasma

  • Placebo comparator
    Placebo

    Participants receive 1 unit of saline with multivitamin.

    Biological: Saline

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..

06

What researchers measure

Primary outcomes

  1. 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

  2. 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

Secondary outcomes

  1. 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

  2. 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

  3. Number of Hospital-free Days During the 30 Days Following Randomization

    Time frame: 30 days

  4. All-cause Mortality

    Time frame: Assessed at 30 days

07

Results

Posted Oct 19, 2021
Limitations and caveats
This study did not meet its maximum sample size of 900 participants due to a planned interim analysis that indicated that it was unlikely that there would be a difference in the rate of disease progression between the two groups if continued to the planned sample size.

Participant flow

Patients were enrolled at 48 hospital emergency departments in 21 states.

Participant flow — Overall Study
MilestoneConvalescent PlasmaPlacebo
Started257254
Intention-to-treat population257254
Had data for 15-day outcome257254
Completed250251
Not completed73
Withdrew: Withdrawal by subject22
Withdrew: Death51

Outcome measures

PrimaryNumber 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
Reported as:
Count of participants · Participants
Number of Patients With Disease Progression (Intention-to-treat Population)
ParticipantsConvalescent PlasmaPlacebo
Patients with a disease-progression event7781
Hospital admission for any reason5156
Seeking emergency or urgent care2525
Death without hospitalization10
Statistical analysis
  • Convalescent Plasma vs Placebo ·
  • Convalescent Plasma vs Placebo · Risk difference (rd): 2.2 · 95% CI -5.9 to 10.4Risk difference after adjustment for age, sex, symptom duration.
PrimaryNumber 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
Reported as:
Count of participants · Participants
Number of Patients With Disease Progression (Per-protocol Population)
ParticipantsConvalescent PlasmaPlacebo
Patients with a disease-progression event7180
Hospital admission for any reason4755
Seeking emergency or urgent care2425
Death without hospitalization00
Statistical analysis
  • Convalescent Plasma vs Placebo ·
SecondaryWorst 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
Reported as:
Count of participants · Participants
Worst Severity Rating on the WHO COVID Ordinal Scale for Clinical Improvement During the 30 Days Following Randomization
ParticipantsConvalescent PlasmaPlacebo
Severity rating 15555
Severity rating 2141133
Severity rating 31217
Severity rating 42835
Severity rating 565
Severity rating 610
Severity rating 722
Severity rating 851
SecondaryNumber 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
Reported as:
Count of participants · Participants
Number of Patients With Worsening of Symptoms at Day 15 as a Measure of Time to Disease Progression
ParticipantsConvalescent PlasmaPlacebo
Number of Patients With Worsening of Symptoms at Day 15 as a Measure of Time to Disease Progression107116
Statistical analysis
  • Convalescent Plasma vs Placebo · Hazard ratio (hr): 0.90 · 95% CI 0.69 to 1.17
SecondaryNumber of Hospital-free Days During the 30 Days Following Randomization
Time frame:
30 days
Reported as:
Mean · days
Number of Hospital-free Days During the 30 Days Following Randomization
daysConvalescent PlasmaPlacebo
Number of Hospital-free Days During the 30 Days Following Randomization28.3 ± 4.928.6 ± 3.6
Statistical analysis
  • Convalescent Plasma vs Placebo · Mean difference (final values): 0.3 · 95% CI -0.4 to 1.1
SecondaryAll-cause Mortality
Time frame:
Assessed at 30 days
Reported as:
Count of participants · Participants
All-cause Mortality
ParticipantsConvalescent PlasmaPlacebo
All-cause Mortality51

Adverse events

Collected over 30 days. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Convalescent Plasma5/257 (1.9%)59/257 (23%)51/257 (19.8%)
Placebo1/254 (0.4%)64/254 (25.2%)35/254 (13.8%)
Most frequent serious events
Showing 10 of 33
Most frequent serious events
EventConvalescent PlasmaPlacebo
PneumoniaInfections and infestations30/25739/254
DyspneaRespiratory, thoracic and mediastinal disorders1/2578/254
HypoxiaRespiratory, thoracic and mediastinal disorders6/2575/254
Infusion related reactionInjury, poisoning and procedural complications4/2570/254
Acute respiratory failureRespiratory, thoracic and mediastinal disorders3/2572/254
Pulmonary embolismRespiratory, thoracic and mediastinal disorders3/2572/254
VomitingGastrointestinal disorders2/2570/254
DehydrationMetabolism and nutrition disorders2/2571/254
AnaemiaBlood and lymphatic system disorders0/2571/254
TachycardiaCardiac disorders0/2571/254
Most frequent other events
Showing 10 of 36
Most frequent other events
EventConvalescent PlasmaPlacebo
Infusion related reactionInjury, poisoning and procedural complications11/2571/254
DyspneaRespiratory, thoracic and mediastinal disorders5/2579/254
Chest painGeneral disorders3/2577/254
PneumoniaInfections and infestations7/2571/254
VomitingGastrointestinal disorders1/2573/254
CoughRespiratory, thoracic and mediastinal disorders0/2573/254
HypoxiaRespiratory, thoracic and mediastinal disorders0/2573/254
MigraineNervous system disorders3/2571/254
Abdominal painGastrointestinal disorders1/2572/254
Coronavirus test positiveInvestigations1/2572/254

Baseline characteristics

Age, Continuous
Age, Continuous(years)Convalescent PlasmaPlaceboTotal
Median54 (42 to 62)54 (40 to 62)54 (41 to 62)
Sex: Female, Male
Sex: Female, Male(Participants)Convalescent PlasmaPlaceboTotal
Female135139274
Male122115237
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Convalescent PlasmaPlaceboTotal
Hispanic or Latino8373156
Not Hispanic or Latino170179349
Unknown or Not Reported426
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Convalescent PlasmaPlaceboTotal
Asian81018
Black4954103
Other282553
White172165337
Region of Enrollment
Region of Enrollment(Participants)Convalescent PlasmaPlaceboTotal
United States257254511
Eligibility risk factor
Eligibility risk factor(Participants)Convalescent PlasmaPlaceboTotal
Age .50 yr155155310
Body-mass index ≥30152150302
Hypertension105111216
Current or former tobacco use8171152
Diabetes mellitus7666142
COPD or asthma5668124
Coronary artery disease282351
Immunosuppression331750
Chronic lung disease161531
Chronic kidney disease161228
Congestive heart disease91120
Currently pregnant336
Organ transplant recipient505
Active cancer224
Sickle-cell disease101
Number of eligibility risk factors
Number of eligibility risk factors(Participants)Convalescent PlasmaPlaceboTotal
15166117
36565130
≥3141123264
Other coexisting illness
Other coexisting illness(Participants)Convalescent PlasmaPlaceboTotal
Current or former alcohol abuse201636
Current or former drug abuse181735
Thromboembolic disorder151025
Liver disease12618
Other hematologic disorder9817

2 further baseline measures are reported on the registry.

08

Study locations

53 sites
  • Chandler Regional Medical Center
    Chandler, Arizona 85224, United States
  • Valleywise Health Medical Center
    Phoenix, Arizona 85008, United States
  • UCSD Health La Jolla
    La Jolla, California 92037, United States
  • Loma Linda University Medical Center
    Loma Linda, California 92354, United States
  • Ronald Reagan UCLA Medical Center
    Los Angeles, California 90095, United States
  • Cedars-Sinai Medical Center
    Los Angeles, California 90211, United States
  • UC Davis Medical Center
    Sacramento, California 95817, United States
  • Stanford University
    Stanford, California 94305, United States
  • Harbor-UCLA Medical Center
    Torrance, California 90502, United States
  • University of Colorado Hospital
    Aurora, Colorado 80045, United States
  • UF Health Shands Hospital
    Gainesville, Florida 32608, United States
  • Jackson Memorial Hospital
    Miami, Florida 33136, United States
  • Grady Memorial Hospital
    Atlanta, Georgia 30303, United States
  • Rush University Medical Center
    Chicago, Illinois 60612, United States
  • University of Illinois Hospital
    Chicago, Illinois 60612, United States
  • University of Chicago Medical Center
    Chicago, Illinois 60637, United States
  • University of Iowa Hospitals & Clinics
    Iowa City, Iowa 52242, United States
  • University of Louisville Hospital
    Louisville, Kentucky 40202, United States
  • Maine Medical Center
    Portland, Maine 04102, United States
  • Tufts Medical Center
    Boston, Massachusetts 02111, United States
  • Beth Israel Deaconess Medical Center
    Boston, Massachusetts 02215, United States
  • Newton-Wellesley Hospital
    Newton, Massachusetts 02462, United States
  • Baystate Medical Center
    Springfield, Massachusetts 01199, United States
  • University of Michigan University Hospital
    Ann Arbor, Michigan 48109, United States
  • Detroit Receiving Hospital
    Detroit, Michigan 48201, United States
  • Harper University Hospital
    Detroit, Michigan 48201, United States
  • Henry Ford Hospital
    Detroit, Michigan 48202, United States
  • Sinai-Grace Hospital
    Detroit, Michigan 48235, United States
  • Spectrum Health Hospitals Butterworth Hospital
    Grand Rapids, Michigan 49503, United States
  • William Beaumont Hospital
    Royal Oak, Michigan 48073, United States
  • William Beaumont Hospital-Troy
    Troy, Michigan 48085, United States
  • HealthPartners Methodist Hospital
    Saint Louis Park, Minnesota 55426, United States
  • Regions Hospital
    Saint Paul, Minnesota 55101, United States
  • Barnes Jewish Hospital
    Saint Louis, Missouri 63110, United States
  • Cooper University Hospital
    Camden, New Jersey 08103, United States
  • Robert Wood Johnson University Hospital
    New Brunswick, New Jersey 08901, United States
  • University of New Mexico Hospital
    Albuquerque, New Mexico 87106, United States
  • SUNY Downstate Medical Center
    Brooklyn, New York 11203, United States
  • Duke University Hospital
    Durham, North Carolina 27710, United States
  • Wake Forest Baptist Medical Center
    Winston-Salem, North Carolina 27103, United States
  • University of Cincinnati Medical Center
    Cincinnati, Ohio 45219, United States
  • OSU Wexner Medical Center
    Columbus, Ohio 43210, United States
  • Mercy St. Vincent Medical Center
    Toledo, Ohio 43608, United States
  • Oregon Health & Science University Hospital
    Portland, Oregon 97239, United States
  • Geisinger Medical Center
    Danville, Pennsylvania 17822, United States
  • Temple University Hospital
    Philadelphia, Pennsylvania 19140, United States
  • Einstein Medical Center
    Philadelphia, Pennsylvania 19141, United States
  • UPMC Presbyterian Hospital
    Pittsburgh, Pennsylvania 15213, United States
  • William P. Clements Jr. University Hospital
    Dallas, Texas 75235, United States
  • Ben Taub General Hospital
    Houston, Texas 77030, United States
  • Memorial Hermann Texas Medical Center
    Houston, Texas 77030, United States
  • University of Utah Healthcare
    Salt Lake City, Utah 84132, United States
  • Froedtert Hospital
    Milwaukee, Wisconsin 53226, United States
09

References and documents

Publications

  • Korley FK, Durkalski-Mauldin V, Yeatts SD, Schulman K, Davenport RD, Dumont LJ, El Kassar N, Foster LD, Hah JM, Jaiswal S, Kaplan A, Lowell E, McDyer JF, Quinn J, Triulzi DJ, Van Huysen C, Stevenson VLW, Yadav K, Jones CW, Kea B, Burnett A, Reynolds JC, Greineder CF, Haas NL, Beiser DG, Silbergleit R, Barsan W, Callaway CW; SIREN-C3PO Investigators. Early Convalescent Plasma for High-Risk Outpatients with Covid-19. N Engl J Med. 2021 Nov 18;385(21):1951-1960. doi: 10.1056/NEJMoa2103784. Epub 2021 Aug 18. PubMed 34407339 ↗

Study documents

  • Protocol and statistical analysis plan · Feb 16, 2021
  • Informed consent form · Nov 4, 2020

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — The complete de-identified patient data set will be shared.

Supporting information: Study protocol, Sap, Icf

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Oct 19, 2021, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT04355767
Lead sponsor
Stanford University
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), Strategies to Innovate EmeRgENcy Care Clinical Trials Network, University of Pittsburgh, Medical University of South Carolina
Responsible party
Sponsor
First posted
Apr 21, 2020
Start date
Aug 11, 2020
Primary completion
Mar 29, 2021
Completion
Mar 29, 2021
Results posted
Oct 19, 2021
Last update
Oct 19, 2021

Study contacts

Clifton W Callaway, MD, PhD
principal investigator · University of Pittsburgh
Valerie Durkalski-Mauldin, PhD
principal investigator · Medical University of South Carolina
Frederick Korley, MD, PhD
principal investigator · University of Michigan
Sharon Yeatts, PhD
principal investigator · Medical University of South Carolina
Robert Silbergleit, MD
principal investigator · University of Michigan
William Barsan, MD
principal investigator · University of Michigan
Kevin Schulman, MD
study director · Stanford University

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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