A randomized, double blinded clinical trial of convalescent plasma compared to standard plasma for treatment of hospitalized non-IC patients with COVID-19 infections

The present COVID-19 pandemic overwhelmes the care-systems of the world and
leads to high morbidity and mortality. No effective therapy or vaccination
strategies are presently available, and outcome is largely dependent on a
fast-enough clearance of the virus by the patients* own immune system. Most
viral infections in this respect lead to a humoral immune response which
consists out of the formation of virus inactivating and neutralizing
antibodies. Also, patients that recover from COVID-19 infections show such
antibodies in their plasma. Hence, assessing the potential therapeutic use of
this plasma for transfusion and thus transfer of antibodies of cured patients
to patients with active disease is logical and the aim of the present trial.

To evaluate the efficacy of convalescent plasma compared to standard plasma to
improve an ordinal outcome as primary endpoint: consisting of shorter than the
average of 6 days hospital stay, no admission to the intensive care unit (ICU),
no need for mechanical ventilation and survival. 2) To compare other efficacy
parameters and safety of convalescent plasma versus standard plasma. 3) To
evaluate the predictive value of co-morbidities and inflammation markers on
endpoints. 4) To evaluate the predictive value plasma characteristics (e.g.
titer and type of anti-Severe Acute Respiratory Disease-Coronavirus- 2
(SARS-CoV-2) titers) on endpoints. 5) To evaluate how convalescent plasma with
anti-SARS-CoV-2 antibodies, modulates course and titres of anti-SARS-CoV-2 in
patients prior to transfusion and thereafter on days 1, 2, 3 and every week up
to day 28 and at day 56 and how this compares to patients transfused with
standard plasma. 6) Compare the rates, levels and duration of SARS-CoV-2 RNA in
nasopharyngeal (NP) swabs using reverse transcription polymerase chain reaction
(RT-PCR) amongst the convalescent plasma and the control (standard plasma)
groups on days 1, 2, 3 and every week up to day 28 and at day 56.

This is a randomized, prospective, multicenter, double blinded phase 2/3 trial
comparing efficacy and safety of anti-SARS-CoV-2 convalescent plasma vs
standard plasma in maximally 3 days hospitalized COVID-19 patients that are not
at or bound to be referred to the ICU.

Enrolled patients will either receive convalescent thawed fresh frozen plasma 1
unit (250-325 ml) (=treatment group) or standard thawed fresh frozen plasma 1
unit (250-325 ml) (=control group).

All patients will receive 1 unit of plasma. Plasma itself has a well known but
minor risk profile. Moreover, most of standard plasma associated side effects
can be avoided by additional measures and exclusion of patients with risk
factors e.g. for transfusion associated circulatory overload (TACO). Treatment
with so called convalescent plasma with COVID-19 antibodies includes the same
minor risk profile as standard plasma infusions, but is conceptually benefical
for additional clearing virus for the transfused patients. However, possible
disease excacerbation by the antibodies has also been suggested. A blinded and
randomized approach comparing standard plasma with convalescent plasma is
therefore chosen, moreover while unbiassed assessment of endpoints is
guaranteed by this stragegy. except for minimal additional blood sampling :
27ml at t=1 (before plasmatransfusion), 28 en 56 days and 8 x6 ml t=1,
2,3,7,14,21, 28, 56 days = 48 ml in total 129 ml, and additional 7viral RNA
assessing nose/pharyngeal swabs. For survival assessment also an on average 3
post-discharge (estimated to be applicable for most patients) visits at day 14,
28, 56 are needed. All other study-related screening and monitoring involves
standard patient care and are according to the WHO/ ISARIC data-dictionary.