A Randomised Open-Label Trial of Early, Very High-Titre Convalescent Plasma Therapy in Clinically Vulnerable Individuals with Mild COVID-19

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic has
caused more than 5 million deaths worldwide. Mortality is 40% or more for
patients from clinically vulnerable groups admitted to hospital. Therefore,
treatment is urgently needed soon after symptom onset, to prevent progression
to severe disease and hospitalization. This is especially important in
clinically vulnerable patients who are at high risk of prolonged
hospitalization or death due to COVID-19.
Furthermore, patients with immunosuppression usage or a immunodeficiency have
been disproportionately affected by the COVID-19 pandemic, and often present
with a persistent SARS-CoV-2 infection and may shed viable SARS-CoV-2 for
months. Vulnerable patients may belong to subgroups less likely to respond well
to vaccination.

We will evaluate the efficacy of convalescent plasma collected from donors with
high-titer neutralizing SARS-CoV-2 antibodies in reducing the risk of
hospitalization in people with early onset COVID-19 compared to standard care.
We will do this through a randomized, open-label two-arm trial in clinically
vulnerable patients that will provide robust comparative efficacy data in
groups most likely to benefit from early treatment. We will assess virologic
parameters by sequentially measuring SARS-CoV-2 RNA and virus viability in
oropharyngeal samples, antibody levels and viral sequence variation.

To determine whether convalescent plasma collected from donors who have
recovered from COVID-19 and who have a very high titre of anti-SARS-CoV-2
antibodies reduce the risk of hospitalization or death due to COVID-19 in
patients with early symptoms of acute COVID-19 who are vulnerable to this
disease compared to standard of care.

Multicenter, randomized, open-label, adaptive superiority trial: convalescent
plasma with a very high neutralizing titer versus standard care in 2 cohorts of
vulnerable patients (cohort 1: elderly (>= 70 years) and younger with
comorbidities, cohort 2: immunosuppressed patients).

Study phase: phase 3
Randomization: 1:1 (standard of care + convalescent plasma vs. standard of
care) stratified by center and by patient cohort
Sample Size: minimum of 340 per cohort and maximum of 1020 per cohort depending
on the interim analysis
Study duration: step 1: 18 months; step 2: 18 to 30 months
Study setting: outpatient setting with recruitment and inclusion in the study
at the hospital

Two units of high antibody titre COVID-19 convalescent plasma to individuals
randomised to the intervention group, 2 units from 2 different donors,
preferably transfused on the same day.

Known potential risks are mostly those associated with the transfusion of
plasma. Adverse effects associated with plasma transfusion CCP include allergy,
febrile reactions, transfusion-related circulatory overload (TACO) and
Transfusion Related Acute Lung Injury (TRALI).
Data show that convalescent plasma is well tolerated. In a Cochrane review,
amongst 20 000 people with COVID-19 receiving convalescent plasma in non*
controlled non*randomized studies of interventions and for whom adverse events
were recorded, there were 63 deaths of which 12 were possibly and 1 probably
related to transfusion (13/20622, 0.06%). There were 146 serious adverse events
within 4 hours and 1136 serious adverse events within 7 days post-transfusion;
predominantly allergic, respiratory, thrombotic or cardiac events (1282/20 000,
6.4%). Four RCTs observed severe or serious transfusion*related adverse events
in 0 to 1.3% of participants receiving convalescent plasma, including severe
transfusion*associated dyspnea, and probably*transfusion*related deaths. The
reported studies pertaining to early convalescent plasma administration in
mildly ill vulnerable COVID-19 patients (as for patients to be included in
COVIC-19) reported no adverse events, or adverse events occurring with similar
frequency in the control groups.

Early transfusion of high titer convalescent plasma in vulnerable patients may
significantly reduce the risk of disease worsening and need for
hospitalization. Severe COVID-19 disease in vulnerable patients such as elderly
patients, less elderly with comorbidities or patients with immunodeficiency
remains associated with significant morbidity and mortality. Furthermore,
immunosuppressed patients, least likely to benefit from a SARS-CoV-2 vaccine,
are at risk of prolonged (>2 months) shedding and pose a risk of sustained
onward transmission or selection of variants and so may gain additional
benefits from early therapeutic intervention. Additionally, reducing the need
for hospitalization will also reduce the burden on the healthcare system at
time of crisis.
To the difference of anti-SARS-CoV-2 monoclonal antibodies, convalescent plasma
may be readily available and adapted in the presence of an emerging
immune-resistant SARS-CoV-2 variant or in case of a pandemic involving a novel
pathogen. The polyclonal antibody content of convalescent plasma could make
this an ideal passive immunotherapy for treatment of patients infected by new
variants.