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Convalescent plasma in patients admitted to hospital with
COVID-19 (RECOVERY): a randomised controlled, open-label,
platform trial
RECOVERY Collaborative Group*
Summary
Background Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies.
We aimed to evaluate the safety and ecacy of convalescent plasma therapy in patients admitted to hospital with
COVID-19.
Methods This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy
[RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is
underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to
receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent
plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is
registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.
Findings Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible
to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group.
There was no significant dierence in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the
convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00,
95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients,
including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent
plasma had no significant eect on the proportion of patients discharged from hospital within 28 days
(3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99,
95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was
no significant dierence in the proportion of patients meeting the composite endpoint of progression to invasive
mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of
5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79).
Interpretation In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or
other prespecified clinical outcomes.
Funding
UK Research and Innovation (Medical Research Council) and National Institute of Health Research.
Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
Introduction
A substantial proportion of individuals with SARS-CoV-2
require hospital care, which can progress to critical illness
with hypoxic respiratory failure. In patients with severe
COVID-19, immunomodulation with corticosteroids and
IL-6 receptor antagonists has been shown to improve
survival.
1,2
Treatments that eectively inhibit viral replica-
tion might reduce tissue damage and allow time for the
host to develop an adaptive immune response that can
clear the infection. However, no treatment directed against
the virus has been shown to reduce mortality (although
remdesivir might shorten the duration of hospital stay).
3
Humoral immunity is a key component of the immune
response to SARS-CoV-2, and it matures over several
weeks following infection. Anti-SARS-CoV-2 antibodies
are detectable at a mean of 13 days after symptom onset,
but neutralising titres do not peak until day 23, and there
is wide variation in both the timing of seroconversion
and peak antibody concentrations between infected
individuals.
4
Although patients with severe COVID-19
generally have higher final antibody concentrations than
those with mild disease, their antibody responses are
delayed.
5
Antibodies might modulate acute viral disease
either through a direct antiviral eect—by binding and
neutralising free virus—or indirectly by activating
antiviral pathways—such as the complement cascade,
phagocytosis, and cellular cytotoxicity. Conversely, there
is also a possibility that antibodies might enhance disease,
either by promoting viral entry or by proinflammatory
mechanisms, such as Fcγ receptor stimulation.
6
Convalescent plasma has been used for more than
100 years as passive immunotherapy for influenza
pneumonia, and more recently for SARS-CoV.
7
Although
observational studies have suggested that convalescent
Lancet 2021; 397: 2049–59
Published Online
May 14, 2021
https://doi.org/10.1016/
S0140-6736(21)00897-7
See Comment page 2024
*The writing committee and trial
steering committee are listed at
the end of this manuscript and a
complete list of collaborators in
the RECOVERY trial is provided in
the appendix (pp 2–28)
Correspondence to:
Prof Peter W Horby and
Prof Martin J Landray, RECOVERY
Central Coordinating Office,
Oxford OX3 7LF, UK
recoverytrial@ndph.ox.ac.uk
See Online for appendix
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plasma might reduce mortality in severe viral respira tory
infections evidence from randomised trials remains
scarce and inconclusive.
8
Convalescent plasma has been
used widely outside of clinical trials, including by more
than 100 000 patients in the US Food and Drugs
Administration (FDA) Expanded Access Program.
9
An
observational analysis of 3082 patients in this programme
reported that in patients who had not received mechanical
ventilation, 30-day mortality was lower in those transfused
with higher-titre plasma (containing higher concentrations
of anti-SARS-CoV-2 spike IgG) compared with those who
received lower-titre plasma.
10
A number of randomised
trials of convalescent plasma in patients hospitalised with
COVID-19 have been reported, but these trials have all
been small and inconclusive.
11–20
Moreover, patients who
are hospitalised with COVID-19 are heterogeneous and
any benefit of convalescent plasma could depend on the
stage of disease, perhaps being restricted to those with
milder disease early in the course of their illness or those
who have not mounted an eective antibody response.
14
Therefore, the ecacy of convalescent plasma as a
treatment for patients hospitalised with COVID-19 is
uncertain. We aimed to evaluate the ecacy and safety
of convalescent plasma in patients hospitalised with
COVID-19.
Methods
Study design and participants
The RECOVERY trial is an investigator-initiated, indi-
vidually randomised, controlled, open-label, adaptive
platform trial to evaluate the eects of potential treat ments
in patients hospitalised with COVID-19. Details of the
trial design and results for other evaluated treatments
(dexamethasone, hydroxychloroquine, lopinavir–ritonavir,
azithromycin, and tocilizumab) have been published
previously.
2
The trial is underway at 177 NHS hospital
organisations in the UK (appendix pp 5–28), supported by
the National Institute for Health Research Clinical Research
Network. The trial was coordinated by the trial sponsor, the
Nueld Department of Population Health, University of
Oxford (Oxford, UK). The trial is being done in accordance
with the principles of the International Conference on
Harmonisation–Good Clinical Practice guidelines and
approved by the UK Medicines and Healthcare products
Regulatory Agency and the Cambridge East Research
Ethics Committee (20/EE/0101). The protocol, statistical
analysis plan, and additional information are available
online and in the appendix (pp 66–151).
Hospitalised patients of any age were eligible for the
trial if they had clinically suspected or laboratory-
confirmed SARS-CoV-2 infection and no medical history
that might, in the opinion of the attending clinician, put
them at significant risk if they were to participate in the
trial. Written informed consent was obtained from all
patients or from their legal representative if they were too
unwell or unable to provide consent.
Randomisation and masking
Baseline data were collected using a web-based case
report form that included demographics, level of
respiratory support, major comorbidities, suitability of
the trial treatment for a particular patient and treatment
availability at the trial site (appendix pp 35–37). Patients
had a serum sample taken before random assignment
for the purpose of assessing the presence of antibodies
against SARS-CoV-2.
Research in context
Evidence before this study
We searched the MEDLINE, Embase, MedRxiv, and bioRxiv
databases from Sept 1, 2019, to March 23, 2021, for randomised
trials or meta-analyses of trials evaluating the effect of
convalescent plasma in patients hospitalised with COVID-19
using the search terms (“COVID-19”, “COVID”, “SARS-CoV-2”,
“2019-nCoV”, or “Coronavirus”) and (“convalescent plasma” ,
“hyperimmune plasma”, “immune plasma”, “passive
immunization”, or “plasma therapy”). 12 trials were identified.
Two trials were excluded from the meta-analysis: one trial of
49 patients that did not have robust allocation concealment and
one trial of 30 patients that did not report mortality. In two trials
participants and clinicians were masked to treatment allocation
and the remaining eight trials were open-label. There was some
concern about missing outcome data in one trial, but the
remaining nine studies were assessed as having a low risk of bias
when using an outcome of mortality. These trials included
1495 randomly assigned patients, of whom 218 died. Most of
these studies recruited patients shortly after admission to
hospital, as was the case in RECOVERY.
Added value of this study
RECOVERY is the largest randomised trial to report results of
the effect of convalescent plasma in patients hospitalised with
COVID-19. We found that compared with usual care alone,
high-titre convalescent plasma did not reduce 28-day
mortality, the probability of discharge within 28 days, or the
probability of progressing to the composite outcome of
invasive mechanical ventilation or death in patients who were
not receiving invasive mechanical ventilation at randomisation.
We saw no evidence of any material benefit or hazard of
convalescent plasma in any patient subgroup. Taking the results
of all trials together, including RECOVERY which includes about
eight-times as much information as all other trials combined,
allocation to convalescent plasma was associated with a
mortality rate ratio 0·98 (95% CI 0·91–1·06; p=0·63).
Implications of all the available evidence
For patients admitted to hospital with COVID-19,
convalescent plasma offers no material therapeutic benefits.
For the protocol, statistical
analysis plan, and additional
information see https://
www.
recoverytrial.net
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Until Sept 18, 2020, eligible and consenting patients
were randomly assigned (1:1) to receive either usual care
(usual care group) or usual care plus convalescent plasma
(conva lescent plasma group). From Sept 18, 2020, patients
were randomly assigned (1:1:1) to the usual care group,
convalescent plasma group, or to receive usual care
plus REGN-COV2 (a combination of two monoclonal
antibodies directed against SARS-CoV-2 spike protein;
appendix pp 35–37). The REGN-COV2 evaluation is
ongoing and not reported here. Random assignment was
unstratified and done by local clinical or research sta
using a web-based interface with allocation concealment
(appendix pp 33–34). For some patients, convalescent
plasma was either declined, unavailable at the trial site at
the time of enrolment, or considered in the opinion of
the attending doctor to be definitely contraindicated (eg,
known moderate or severe allergy to blood components).
These patients were not included in the comparison of
convalescent plasma versus usual care.
In a factorial design, patients could be simultaneously
randomly assigned to other treatment groups: (1) hydroxy-
chloroquine or dexamethasone or azithromycin or
lopinavir–ritonavir or colchicine versus usual care, and
(2) aspirin versus usual care (appendix pp 33–34). The
trial also allowed a subsequent randomisation for patients
with progressive COVID-19 (evidence of hypoxia and a
hyperinflammatory state) to tocilizumab versus usual
care. Participants and local study sta were not masked
to the allocated treatment. Several of these treatment
groups were added to or removed from the protocol
over the period that convalescent plasma was evaluated
(appendix pp 29–34). The trial steering committee,
investigators, and all other indi viduals involved in the
trial were masked to outcome data during the trial.
Procedures
Convalescent plasma donors were recruited and screened
by the four UK blood services: NHS Blood and Transplant,
the Northern Ireland Blood Transfusion Service, the
Scottish National Blood Transfusion Service, and the
Welsh Blood Service (appendix pp 2–4, 29). Only plasma
donations with a sample to cuto ratio of 6·0 or more
on the EUROIMMUN IgG enzyme-linked immuno-
sorbent assay (ELISA) targeting the spike glycoprotein
(PerkinElmer, London, UK) were supplied for the
RECOVERY trial (appendix p 29). EUROIMMUN IgG
has been shown to correlate well with neutralisation
assays, and a sample to cuto ratio of 6·0 or more was
previously shown to be associated with neutralising titres
of 1:100 or more in convalescent plasma.
21–24
The US FDA
has determined that convalescent plasma with a
EUROIMMUN sample to cuto of 3·5 or more qualifies
as high titre and can be used for the treatment of
hospitalised patients under an Emergency Use Authorisa-
tion.
9
Patients in the convalescent plasma group received
two units (275 ml [200–350]) intra venously, the first as
soon as possible after randomisation and the second
(from a dierent donor) the following day and at least 12 h
after the first.
Early safety outcomes were recorded by site sta using an
online form 72 h after randomisation (appendix pp 38–42).
An online follow-up form was completed by site sta
when patients were discharged, had died, or at 28 days
after ran domisation, whichever occurred first (appendix
pp 43–49). Informa tion was recorded on adherence to
allocated trial treat ment, receipt of other COVID-19 treat-
ments, duration of admission, receipt of respiratory or
renal support, and vital status (including cause of death).
In addition, routine health-care and registry data were
obtained, including information on vital status at day 28
(with date and cause of death); discharge from hospital; and
receipt of respiratory support or renal replacement therapy.
Baseline SARS-CoV-2 serostatus for each participant
was determined using serum samples taken at the time
of randomisation. Analysis was done at a central
laboratory with a validated 384 well plate indirect ELISA
(appendix p 29).
25
Participants were categorised as
seropositive or seronegative using a predefined assay
threshold with a 99% or higher sensitivity and specificity
in detecting individuals with SARS-CoV-2 infection at
least 20 days previously.
25
Outcomes
Outcomes were assessed at 28 days after randomisation,
with additional analyses specified at 6 months. The
primary outcome was all-cause mortality. Secondary
outcomes were time to discharge from hospital and,
in patients not receiving mechanical ventilation at
random isa tion, subsequent receipt of invasive mecha-
nical ventilation (including extra-corporeal membrane
oxygenation) or death. Prespecified, sub sidiary clinical
outcomes included receipt of ventila tion, time to
successful cessation of invasive mechanical ventilation
(defined as removal of invasive mechanical ventilation
within, and survival to, 28 days), and use of renal dialysis
or haemofiltration.
Prespecified safety outcomes were transfusion related
adverse events at 72 h following randomisation
(worsening respiratory status, suspected transfusion
reaction, fever, hypotension, haemolysis, and thrombotic
events), cause-specific mortality, and major cardiac
arrhythmia. Information on serious adverse reactions
to convalescent plasma was collected in an expedited
fashion via the existing NHS Serious Hazards of
Tranfusion haemovigilence scheme.
Statistical analysis
In accordance with the statistical analysis plan, an
intention-to-treat comparison was done between patients
in the convalescent plasma group and those in the usual
care group for whom convalescent plasma was both
available and suitable as a treatment. For the primary
outcome of 28-day mortality, the log-rank observed minus
expected statistic and its variance were used both to test
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the null hypothesis of equal survival curves (ie, the
log-rank test) and to calculate the one-step estimate of
the average mortality rate ratio. We used Kaplan-Meier
survival curves to display cumulative mortality over the
28-day period. We used similar methods to analyse time to
hospital discharge and successful cessation of invasive
mechanical ventilation, with patients who died in hospital
right-censored on day 29. Median time to discharge was
derived from Kaplan-Meier estimates. For the prespecified,
composite, secondary outcome of progression to invasive
mechanical ventilation or death within 28 days (in those
not receiving invasive mechanical ventilation at ran-
domisation) and the subsidiary clinical outcomes of
receipt of ventilation and use of haemo dialysis or
haemofiltration, the precise dates were not available so the
risk ratio was estimated instead.
Prespecified analyses of the primary outcome were
done in seven subgroups defined by characteristics at
randomisation: age, sex, ethnicity, respiratory support
received, days since symptom onset, use of systemic
corticosteroids, and presence of anti-SARS-CoV-2
anti body. Observed eects within these subgroup
categories were compared using a χ² test. Subgroup
analyses according to these baseline characteristics
were also done for the secondary outcomes. Post-hoc
exploratory analyses of the primary outcome included
examination by days since symptom onset, using four
subcategories rather than the two that were prespecified,
and level of respiratory support by subdividing the
oxygen only group into three subcategories. In late
2020, a new SARS-CoV-2 variant, named B.1.1.7, with
multiple substitutions in the receptor binding domain
of the spike glycoprotein emerged in southeast England
and rapidly grew to become the dominant virus variant
throughout the UK.
26
Conva lescent plasma from
individuals infected before the emergence of B.1.1.7
show a modest reduction in ability to neutralise B.1.1.7
compared with earlier SARS-CoV-2 virus variants.
27
The clinical significance of this reduced in-vitro
neutralisation is not known. To assess if there was
evidence of a dierence in the eectiveness of con-
valescent plasma before and after the emergence
of B.1.1.7, an additional post-hoc exploratory analysis
was done of the primary outcome comparing eects in
patients randomly assigned before Dec 1, 2020, with
those randomly assigned from Dec 1, 2020, onwards.
26
Additional sensitivity analyses included restricting
analysis of the primary outcome to patients with a posi-
tive PCR test for SARS-COV-2 and repeating subgroup
analyses of the primary and secondary outcomes by
presence of anti-SARS-CoV-2 antibody after adjustment
for age. Age adjustment was done because in seronegative
patients those assigned to the convalescent plasma group
were slightly younger than those assigned to the usual
care group, whereas in seropositive patients those
assigned to the convalescent plasma group were slightly
older than those assigned to the usual care group. A
final prespecified exploratory analysis estimated whether
the eect of allocation to convalescent plasma varied
depending on whether the patient was simul taneously
allocated azithromycin (the only other treatment that has
both already reported its results and to which substantial
numbers of patients could have been assigned at the
same time as they were randomly assigned to receive
convalescent plasma or usual care).
Estimates of rate and risk ratios are shown with
95% CIs. All p values are two-sided and are shown
without adjustment for multiple testing. The full
database is held by the trial team who pooled the data
from trial sites and did the analyses at the Nueld
Department of Population Health, University of Oxford.
For the primary outcome of 28-day mortality, the
results from RECOVERY were subsequently included in
a meta-analysis of results from all previous randomised
trials of convalescent plasma versus usual care in
patients with COVID-19. For each trial, we compared the
observed number of deaths among patients allocated
convalescent plasma with the expected number if all
Figure 1: Trial profile
*Number recruited overall during period that patients could be recruited into convalescent plasma comparison.
†Reasons for exclusion are not mutually exclusive. ‡Patients in the group are not included in the analyses of this
study. §5301 of 5795 patients with completed follow-up at time of analysis received convalescent plasma. ¶17 of
5763 patients with completed follow-up at time of analysis received convalescent plasma. ||A second
randomisation to tocilizumab versus usual care in patients with hypoxia and C-reactive protein ≥75 mg/L was
introduced in protocol version 4.0; 426 patients in the convalescent plasma group were randomly assigned to
receive tocilizumab with 486 randomly assigned to receive usual care alone; 573 patients in the usual care group
were randomly assigned to receive tocilizumab with 552 randomly assigned to receive usual care alone.
5795 allocated convalescent plasma§
23 withdrew consent
13
127 eligible for randomisation
to convalescent plasma
11
558 randomised between
convalescent plasma and
usual care
16
287 patients recruited*
912 included in second randomisation||
16 withdrew consent
1125 included in second randomisation||
5763 allocated usual care¶
5795 included in 28-day
intention-to-treat analysis
5763 included in 28-day
intention-to-treat analysis
1569 allocated REGN-COV-2‡
3160 excluded†
965 convalescent plasma unavailable
2764 unsuitable for convalescent plasma
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2053
patients were at equal risk (ie, we calculated the observed
minus expected statistic [o–e], and its variance [v]). For
RECOVERY, these were taken as the log-rank observed
minus expected statistic and its variance but for other
trials, where the exact timing of each death was not
available, these were calculated from standard formulae
for 2 × 2 contingency tables. We then combined trial
results using the log of the mortality rate ratio calculated
as the inverse-variance weighted average S/V with
variance 1/V (and hence with 95% CI S/V ±1·96/√V),
where S is the sum over all trials of (O–E) and V is the
sum over all trials of v. Analyses were done with SAS
(version 9.4) and R (version 3.4).
As stated in the protocol, appropriate sample sizes
could not be estimated when the trial was being planned
at the start of the COVID-19 pandemic. During the
trial, external data suggested that any benefits of
antibody-based therapies might be higher in patients who
had not raised an adequate antibody response of their
own.
14
Consequently, while still masked to the results of
the trial, the RECOVERY steering committee determined
that the trial should enrol sucient patients to provide at
least 90% power at a two-sided p value of 0·01 to detect
a proportional reduction in 28-day mortality of a fifth
in patients with and, separately, without detectable
SARS-CoV-2 antibodies at ran domisation (appendix p 34).
On Jan 7, 2021, the independent data monitoring
committee did a routine review of the data and
recommended that the chief investigators pause
recruitment to the convalescent plasma comparison in
those patients receiving invasive mechanical ventilation
(including extracorporeal membrane oxygenation) at the
time of randomisation. At the same time, the committee
recommended that recruitment to the convalescent
plasma comparison continue for all other eligible patients.
On Jan 14, 2021, the data monitoring committee did
another routine review of the data and notified the chief
investigators that there was no convincing evidence that
continued recruitment would provide conclusive proof
of worthwhile mortality benefit, either overall or in any
prespecified subgroup. The committee recommended
that recruitment to the convalescent plasma portion of
the study should cease and follow-up be completed.
Enrolment of patients to the convalescent plasma
comparison was closed on Jan 15, 2021, and the
preliminary result for the primary outcome was made
public. The trial is registered with ISRCTN, 50189673,
and ClinicalTrials.gov, NCT04381936.
Convalescent plasma
group (n=5795)
Usual care group
(n=5763)
Mean age, years 63·5 (14·7) 63·4 (14·6)
Age groups
<70* 3705 (64%) 3748 (65%)
70–79 1310 (23%) 1281 (22%)
≥80 780 (13%) 734 (13%)
Sex
Men 3643 (63%) 3787 (66%)
Women† 2152 (37%) 1976 (34%)
Ethnicity
White 4493 (78%) 4421 (77%)
Black, Asian, and minority
ethnic
833 (14%) 887 (15%)
Unknown 469 (8%) 455 (8%)
Median number of days since
symptom onset
9 (6–12) 9 (6–12)
Median number of days since
admission to hospital
2 (1–3) 2 (1–4)
Respiratory support received
No oxygen received 442 (8%) 455 (8%)
Oxygen only‡ 5051 (87%) 4993 (87%)
Invasive mechanical
ventilation
302 (5%) 315 (5%)
Previous diseases
Diabetes 1535 (26%) 1569 (27%)
Heart disease 1267 (22%) 1309 (23%)
Chronic lung disease 1385 (24%) 1328 (23%)
Tuberculosis 20 (<1%) 23 (<1%)
HIV 17 (<1%) 19 (<1%)
Severe liver disease§ 70 (1%) 72 (1%)
Severe kidney impairment¶ 323 (6%) 293 (5%)
Any of the above 3203 (55%) 3222 (56%)
(Table 1 continues in next column)
Convalescent plasma
group (n=5795)
Usual care group
(n=5763)
(Continued from previous column)
SARS-CoV-2 PCR test result
Positive 5593 (97%) 5566 (97%)
Negative 126 (2%) 116 (2%)
Unknown 76 (1%) 81 (1%)
Patient SARS-CoV-2 antibody test result
Positive 3078 (53%) 2810 (49%)
Negative 2016 (35%) 1660 (29%)
Missing 701 (12%) 1293 (22%)
Corticosteroids received
Yes 5370 (93%) 5311 (92%)
No 391 (7%) 413 (7%)
Not recorded 34 (1%) 39 (1%)
Other randomised treatments
Lopinavir–ritonavir 5 (<1%) 14 (<1%)
Dexamethasone 3 (<1%) 3 (<1%)
Hydroxychloroquine 1 (<1%) 0
Azithromycin 587 (10%) 585 (10%)
Colchicine 792 (14%) 791 (14%)
Aspirin 1266 (22%) 1207 (21%)
Data are mean (SD), n (%), or median (IQR). *Includes 26 children (<18 years).
†Includes 28 pregnant women. ‡Includes non-invasive ventilation. §Defined as
requiring ongoing specialist care. ¶Defined as estimated glomerular filtration rate
<30 mL/min per 1·73 m².
Table 1: Baseline characteristics
