Terapi Plasma Konvalesen

pada COVID-19
Berdasarkan Hasil Penelitian Terkini

Dr. M. Karyana
Puslitbang Sumber Daya dan Pelayanan Kesehatan

Workshop Pelayanan Darah, Bekasi, 28-30 April 2021

Introduction
• No proven treatment options for coronavirus disease (COVID-19) has
been established
• Augmentation of the humoral immune (antibody) response using
passive immunotherapy is a potentially useful therapeutic approach
to COVID-19
• A variety of studies are examining the role of passive transfer of anti-
SARS-CoV-2 antibodies
• Single donor convalescent plasma
• Hyperimmune Intravenous Immunoglobulin (IVIg)
• Monoclonal antibodies
Passive immunotherapy strategies
Y
Y

Plasma Standard IVIG

donor Y
Y
COVID-19 convalescent
plasma (CCP)
Y Y
Y Y
Hyperimmune COVID-
IVIG (hIVIG)
COVID-19 Y
recovered donor
Y Y YY
Neutralising monoclonal
antibody (nMAb)
Overview of Convalescent Plasma
• Administration of high titer neutralizing immunoglobulin-containing plasma
from recently-recovered COVID-19 survivors
• A perennial favorite in the setting of a new outbreak
• Dating back to the 1918 influenza pandemic; 19th-century treatment for diptheria and
tetanus
• Multiple anecdotes of success in diseases ranging from influenza to SARS to Ebola
• There is great enthusiasm for the use of convalescent plasma for COVID-19; the
approach appears relatively safe with a hint of efficacy in a subset of patients;
RCT data are anxiously awaited
• Earlier administration may increase the effect as passive antibody works by neutralizing the
virus before they shed abundantly
• The use of convalescent plasma with higher antibody levels might be associated with
reduced mortality.
• Possible side effects of COVID-19 convalescent plasma include allergic reactions,
transfusion-associated circulatory overload, and transfusion associated lung
injury, as well as the potential for transfusion-transmitted infections.
Rationale of Convalescent Plasma Therapy
Proposed protective
mechanism of
convalescent plasma:
• Pathogen neutralization
(antiviral)
• Immunomodulatory
effects (anti
inflammatory or control
of overreactive immune
system)
• antibody dependent
cellular cytotoxicity,
• complement activation,
• phagocytosis

(Rojas, July 2020)

US-FDA Status
• Regulated by the FDA through
clinical trials, single patient eINDs,
an Expanded Access Program
(EAP) facilitated by the Mayo Clinic
and, as of August 23 an
Emergency Use Authorization
(EUA).
• The FDA concluded convalescent
plasma 'may be effective.’
• The EUA is not intended to
replace randomized clinical trials
• RCT is critically important for the
definitive demonstration of safety
and efficacy of convalescent https://www.fda.gov/news-events/press-announcements/fda-issues-emergency-use-authorization-
plasma convalescent-plasma-potential-promising-covid-19-treatment
 US-FDA Status
• This EUA authorizes only the use
of high titer COVID-19
convalescent plasma, for the
treatment of hospitalized patients
with COVID-19, early in the course
of disease. The use of low titer
COVID-19 convalescent plasma is
not authorized under this EUA.

https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-applications-inds-cber-regulated-
products/recommendations-investigational-covid-19-convalescent-plasma
Tests Acceptable for Use in
the Manufacture of
High Titer COVID-19
Convalescent Plasma
Dosing Non-intubated patients treated within 72 hrs
of diagnosis; age < 80 years old (n=1018)
Higher titer plasma in patients not intubated:
20% reduction in 7-day mortality (p=0.03)
All patients (n=4470)
7-day mortality
Cutoff at 1:640
54% p=.0005

FDA states a preference for the use of “high titer”

convalescent plasma, as defined by a neutralizing antibody
titer of ≥250 in the Broad Institute's neutralizing antibody
assay or an S/C cutoff of ≥12 in the Ortho VITROS IgG assay,
www.fda.gov
The FDA recommends administering 1 unit of convalescent plasma
(approximately 200 mL) and notes an additional unit may be
considered based on prescriber clinical judgment (FDA Fact Sheet).
Safety
• In the largest safety study to date of
5,000 patients hospitalized with
severe or life-threatening COVID-19
disease, 15 deaths were reported
within 4 hours of transfusion (0.3%),
with 4 deaths (0.08%) considered
possibly or probably related to
convalescent plasma transfusion
• Given the deadly nature of COVID-
19 and the large population of
critically ill patients included in
these analyses, the mortality rate
does not appear excessive. These
early indicators suggest that
transfusion of convalescent plasma
is safe in hospitalized patients with
COVID-19.
(Joyner, May 2020).
Key Literatures
• Overall, observational studies have found both benefit and no benefit
when convalescent plasma is used in hospitalized patients with COVID-19.
• To date, of the several randomized controlled trials examining the use of
convalescent plasma in patients hospitalized with COVID-19, only one was
able to fully enroll; others were under-powered due to low enrollment and
not meeting their target sample size.
• It is therefore unknown if convalescent plasma is beneficial for patients
hospitalized with COVID-19.
• This question is further complicated by a lack of knowledge regarding what
titer of antibody should be administered; many of published studies to date
did not measure donor plasma antibody titers prior to use.
• Based on the published literature, the use of convalescent plasma appears
to be relatively safe.
 1 Effect of Convalescent Plasma Therapy on Time
to Clinical Improvement in Patients With Severe
and Life-threatening COVID-19 A Randomized
Clinical Trial (China)
• Study population:
• 103 patients hospitalized with severe or life-
threatening COVID-19 at seven academic medical
centers in China.
• Patients randomized to receive convalescent plasma
with S-RBD–specific IgG titer of at least 1:640 dilution
and standard of care, or standard of care alone.
• A serum neutralization titer of 1:80 is approximately
equivalent to a titer of 1:1280 for S-RBD– specific IgG
• Standard of care included the following possible
treatments: antiviral medications, antibacterial
medications, steroids, human immunoglobulin,
Chinese herbal medicines or other medications.
• The median time between symptom onset and
randomization was 30 days.
• Primary endpoint:
• Time to clinical improvement within 28 days.
(Li, June 2020)
 (Li, June 2020)
• Key findings:
• Clinical improvement occurred within 28 days in 51.9% (27/52) of the convalescent plasma group vs.
43.1% (22/51) in the control arm (OR, 1.40; p = 0.26).
• In patients with severe disease, clinical improvement at 28 days occurred in 21 patients (91.3%) in the
convalescent plasma group vs. 15 patients (68.2%) in the control arm (OR, 2.15; p= 0.03).
• In patients with life-threatening disease, clinical improvement at 28 days occurred in 20.7% (6/29) of
the convalescent plasma group vs. 24.1% (7/29) of the control arm (HR, 0.88; p = 0.83).
• There was no significant difference in 28-day mortality (15.7% vs. 24.0%; OR, 0.59; p = 0.30) or time
from randomization to discharge (51% vs. 36% discharged by day 28; HR, 1.61; p = 0.12)
(Li, June 2020) – Cont.
• Limitations:
• The study was terminated early due to an inability to recruit 200 patients;
therefore, it may have been underpowered.
• The use of other medications as part of the standard COVID-19 care at the time
was heterogeneous and may have confounded the results.
• Overall, in patients with severe or life-threatening COVID-19,
convalescent plasma therapy with standard of care did not significantly
improve the time to clinical improvement within 28 days.
• In subgroup analysis of patients with severe, but not life-threatening disease,
clinical improvement was seen in patients who received plasma, despite
patients being symptomatic for a median of 33 days in this group (ie, one would
expect they had developed their own neutralizing antibodies by then).
• The numbers of patients in the subgroup analyses were small.
2
A randomized trial comparing convalescent plasma with standard of care
in patients hospitalized for COVID-19 - ConCOVID trial (Netherland)
• Study population:
• 86 patients hospitalized with COVID-19 in the Netherlands who had been symptomatic for a median 10 days at the time of enrollment
received convalescent plasma with antibody titers of >1:80 dilution and standard of care, or standard of care alone.
• Standard of care included chloroquine, azithromycin, lopinavir/ritonavir, tocilizumab, anakinra or other medications.
• Primary endpoint:
• 60-day mortality.
• Key findings:
• 53 of 66 patients had anti-SARS-CoV-2 antibodies at time of enrollment into the study.
• At the time of enrollment, the majority of participants had experienced COVID-19 related symptoms for 10 days (IQR 6 – 15) and had
been admitted to the hospital for 2 days (IQR 1 – 3 days).
• A SARS-CoV-2 plaque reduction neutralization test revealed neutralizing antibodies in 44/56 (79%) patients tested, with median titers
comparable to the 115 donors (1:160 vs. 1:160, p=0.40).
• No difference in mortality (p=0.95), hospital stay (p=0.68) or day-15 disease severity (p=0.58) observed between plasma-treated
patients and those on standard of care.
• The trial was halted early due to concerns about convalescent plasma’s lack of benefit.
• Limitations:
• The study was stopped early and may have been underpowered to detect a benefit.
• The use of other medications as part of the standard COVID-19 care at the time was heterogeneous and may have confounded the
results.
• Overall, patients with COVID-19 may have antibody titers and still be symptomatic. Antibody titers should be
checked in patients prior to the administration of convalescent plasma
(Gharbharan, July 2020)
 • Most COVID-19 patients already have high neutralizing
ConCOVID Trial – antibody titers at hospital admission.
• Screening for antibodies and prioritizing convalescent plasma
Cont. to risk groups with recent symptom onset will be key to
identify patients that may benefit from convalescent plasma.

(Gharbharan, July 2020)

3
An observational, open-label Expanded Access Program for the treatment
of COVID-19 patients with human convalescent plasma (Mayo, US)

• Study population:
• 35,322 hospitalized patients with
severe or life-threatening COVID-
19 at 2,807 U.S. acute care
facilities.
• 52.3% patients in the ICU; 27.5%
received mechanical ventilation.
• Antibody levels in the units
collected were not measured at
the time of transfusion.
• Primary endpoint:
• 7-day and 30-day mortality.

Joyner, August 2020

Key findings:
• The 7-day mortality rate was
8.7% in patients transfused
within 3 days of COVID-19
diagnosis but 11.9% in patients
transfused after 3 days
(p<0.001).
• 30-day mortality was 21.6% vs.
26.7% (p<0.0001).
• The pooled relative risk of
mortality among patients
transfused with high antibody
level plasma units was 0.65
[0.47-0.92] for 7 days and 0.77
[0.63-0.94] for 30 days versus
those transfused with low
antibody level plasma units.
• Earlier transfusion of
convalescent plasma (less than 4
days after diagnosis) and higher
antibody levels was associated
with reduced 7-day and 30-day
mortality.
Joyner, August 2020
• Limitations:
• This is a non-randomized design with no
comparator group—therefore, the presence of
confounding factors cannot be excluded.
• Physicians chose whether to request plasma for
their patients and the timing of plasma
transfusion; selection bias cannot be examined.
• The cut-offs for “low” and “high” antibody titers
were determined after study analysis began,
rather than prior to study initiation.
• Participants received other SARS-CoV-2-related
therapies, such as remdesivir and
dexamethasone. The use of these agents varied
over time.
• Overall, in this non-randomized
observational study, mortality was lower in
patients who received convalescent plasma
within 3 days of diagnosis, as opposed to 4
days after diagnosis
Joyner, August 2020
4
Treatment of COVID-19 patients with convalescent plasma reveals a signal
of significantly decreased mortality (Houston, US)

• Study population:
• Interim analysis of 136 patients transfused with convalescent plasma and matched to 251
non-transfused control COVID-19 patients at Houston Methodist hospitals.
• Primary endpoint:
• 28-day mortality.
• Key findings:
• There was a significant reduction (p=0.047) in 28-day mortality in patients transfused with
convalescent plasma, specifically in patients transfused within 72 hours of admission with
plasma with an anti-spike protein receptor binding domain titer >1:1350.
• Limitations:
• Patients transfused with plasma and in the standard of care arm also received other agents,
including steroids, azithromycin, hydroxychloroquine, remdesivir and tocilizumab, potentially
confounding results.
• This is a non-randomized trial; however, it uses propensity-score matching to control
confounding.
(Salazar, August 2020)
 Salazar, August 2020 – Cont.
• Kaplan-Meier curves for mortality
within 28 days post-day 0 for secondary
matched cohorts.
• A: All secondary matched patients.
• B: Secondary matched patients transfused
within 72 hours of admission.
• C: Secondary matched patients transfused
>72 hours after admission.
• D: Secondary matched patients transfused
within 72 hours of admission with plasma
with Anti receptor binding domain IgG titer
>1:1350.
• Overall, in this interim propensity
score-matched analysis, transfusion of
high anti-receptor binding domain
(RBD) IgG titer COVID-19 convalescent
plasma early in hospitalization was
associated with a reduction in
mortality in COVID-19 patients
5
Convalescent Plasma for COVID-19: A multicenter, randomized clinical
trial - ConPlas-19 Trial (Spain)

• Study population:
• 81 patients hospitalized for COVID-19 in 14 Spanish hospitals.
• The goal enrollment was 278 patients.
• 38 were randomized to convalescent plasma (1 unit = 250-300 mL) + standard of
care; 43 were randomized to standard of care.
• The median age was 59 years; 54.3% of the patients were male.
• Primary endpoint:
• To demonstrate the efficacy and safety of convalescent plasma in preventing
progression to severe disease or death in hospitalized patients with early COVID-19.
• Proportion of patients in categories 5, 6 or 7 of a seven-category COVID-19 ordinal
scale at day 15.
• The ordinal scale was as follows: 1, not hospitalized, no limitations on activities; 2, not
hospitalized, limitation on activities; 3, hospitalized, not requiring supplemental oxygen; 4,
hospitalized, requiring supplemental oxygen; 5, hospitalized, on non-invasive ventilation or
high flow oxygen devices; 6, hospitalized, on invasive mechanical ventilation or ECMO and 7,
death.
(Avendano-Sola, September 2020).
ConPlas -19 – Cont.
• Key findings:
• Median time interval between symptom onset and
randomization was 8 days.
• At baseline 40 out of 81 patients (49.4%) tested
positive for anti-SARS-CoV-2 IgG antibodies.
• Patients assigned to convalescent plasma had a
lower rate of worsening at 15 days than patients
receiving standard of care only.
• There were no patients progressing to mechanical
ventilation or death among the 38 patients
assigned to receive plasma (0%) versus 6 out of 43
patients (14%) progressing in control arm.
• Mortality rates were 0% vs. 9.3% at days 15 and 29
for the active and control groups, respectively.
• Sixteen serious or grade 3-4 AE were reported in 13
patients, 6 in the CP group and 7 in the standard of
care group.
(Avendano-Sola, September 2020).
ConPlas -19 – Cont.
• Limitations:
• The trial was stopped early due to low
enrollment; of a planned 278 patients, only 81
were enrolled.
• Open-label study.
• Baseline characteristics of patients not provided.
• The patients received convalescent plasma over
a week after symptom onset; this may be too
late to see a significant effect.
• The titer of neutralizing antibodies was not
obtained when the convalescent plasma units
were obtained and were not used to select
donors or units.
• Half of the patients were already IgG positive at
the time of enrollment and may have had less of
a benefit from convalescent plasma.
• The real-world clinical implications of the
primary endpoint is not clear.
Overall, in this open-label
randomized study, the administration
of convalescent plasma was
associated with a reduction in the
probability of clinical deterioration,
ICU admission, or death in
hospitalized COVID-19 patients who
did not require highflow oxygen
devices or mechanical ventilation.
However, caution must be
undertaken when interpreting the
results, as the study was stopped
early and under-powered
(Avendano-Sola, September 2020).
6
Convalescent plasma in the management of moderate COVID-19 in India: An open-
label parallel-arm phase II multicentre randomized controlled trial - PLACID Trial

• Study population:
• 464 hospitalized patients with moderate COVID-19 across 39 hospitals in India.
• Primary endpoint:
• Composite outcome of progression to severe disease or all-cause mortality at 28 days.
• Key findings:
• 235 patients were randomized to the intervention arm, and 229 to the control arm.
• The median time from symptom onset to enrollment was 8 days (IQR 6-11) in both arms.
• The composite primary endpoint was achieved in in 44 (18.7%) participants in the intervention arm and
41 (17.9%) in the control arm [aOR: 1.09; 95% CI: 0.67, 1.77].
• Mortality was documented in 34 (14.5%) and 31 (13.5%) participants in intervention and control arm,
respectively [aOR) 1.06 95% CI: 0.61 to 1.83].
• The median titer of neutralizing antibody in the plasma used was 1:40 (IQR 1:30-1:80).
• At days 3 and 5 patients in the intervention arm had a greater absolute reduction in FiO2 compared to
patients in the control arm (5 (0,12) vs. 3.7 (0,9), p=0.04, and 9 (3,17) vs. 7 (0,14), p=0.04).
• Limitations:
• The study was open label, which could have lead to anchoring bias among providers.
• Measurement of antibody titer prior to plasma administration was not done.
• The median titer of antibody in the plasma units used was low. (Agarwal, September 2020)
 c

• Convalescent plasma was not

associated with a reduction in
progression to severe covid-19
or all cause mortality
• Negative conversion of SARS-
CoV-2 RNA at day 7 post
enrolment was significantly
higher in the intervention arm c
compared with control arm
• Their “moderate” COVID-19
illness criteria enrolled in the
study were similar to those
“severe” illness in other
studies

(Agarwal, September 2020)

PLACID Trial – Cont.

• Neutralizing antibody titres did not differ

between the two trial arms despite the
transfusion of convalescent plasma.

• Participants had higher antibody positivity and

median neutralizing antibody titres than the
donors of convalescent plasma.

• The difference in age and severity of illness

between participants, with donors being
younger and having milder disease, could have
driven this difference.

• This suggests potentially no benefit of

convalescent plasma collected from young
survivors of mild covid-19 and administered to
elderly patients with moderate or severe
disease who have a robust antibody response.
(Agarwal, September 2020)

PLACID Trial – Cont.
Overall, in this open-label randomized controlled trial, the
administration of convalescent plasma to hospitalized patients
with moderate COVID-19 did not lead to improvement in a
composite endpoint of disease progression or all-cause
mortality.

• They did not find evidence to support

the immunomodulator functions of
convalescent plasma as they could not
show differences in the levels of
inflammatory markers.
• This could potentially explain why
convalescent plasma treatment made
no difference to the primary outcome
despite early negativity for SARS-CoV-2
RNA

(Agarwal, September 2020)

7 Convalescent plasma treatment of severe COVID-19: a propensity score–
matched control study (Mount Sinai, US)

• Study population:
• 45 hospitalized patients with severe COVID-19.
• 39 of 45 patients were transfused with convalescent plasma with antibody titers of >1:320 dilution.
• Primary endpoint:
• Clinical condition at 14 days.
• Key findings:
• Oxygen requirements on day 14 after transfusion worsened in 17.9% of plasma recipients versus
28.2% of propensity score–matched controls who were hospitalized with COVID-19 (adjusted odds
ratio (OR), 0.86; 95% confidence interval (CI), 0.75–0.98; chi-square test P value = 0.025)
• Survival also improved in plasma recipients (adjusted hazard ratio (HR), 0.34; 95% CI, 0.13–0.89; chi-
square test P = 0.027)
• Subgroup analyses showed significant survival benefits of convalescent plasma in patients who were
not intubated, had a shorter duration of symptoms and received therapeutic anticoagulation.
However, these subgroups were not significantly different from their complementary subgroups (chi-
square test for homogeneity P = 0.207, P = 0.415 and P = 0.306, respectively).
• Limitations:
• This was a small study at a single center with a non-randomized design; despite the use of matching,
bias may still be present.
(Liu, September 2020)
Overall, in this retrospective control
study, the use of convalescent plasma
was associated with improved survival in
non-intubated, early duration of
symptom and anticoagulant therapy
patients
Liu, S.T.H., Lin, H., Baine, I. et al. Convalescent plasma treatment of severe COVID-19: a propensity score–matched control study. Nat Med (2020).
https://doi.org/10.1038/s41591-020-1088-9
Hasil Studi Terkini di Dunia
Argentina

Argentina
 Conclusion
• There are insufficient data to recommend either for or against the use of COVID-19
convalescent plasma for the treatment of COVID-19.
• Despite meeting the “may be effective” criterion for EUA issuance, the EAP analyses
are not sufficient to establish the efficacy or safety of convalescent plasma due to
the lack of a randomized, untreated control group and potential confounding.
• The results of current studies suggest that convalescent plasma with high antibody
titers may be more beneficial in non-intubated patients, particularly when
administered within 72 hours of COVID-19 diagnosis.
• There is no widely available and generally agreed-upon best test for measuring
neutralizing antibodies, and the antibody titers of plasma from patients who have
recovered from COVID-19 are highly variable.
• Hospitalized patients with COVID-19 may already have SARS-CoV-2 neutralizing
antibody titers that are comparable to those of plasma donors, potentially limiting
the benefit of convalescent plasma in this patient population.
• Additional clinical trials are underway to further examine these questions, as are
trials using convalescent plasma in the outpatient setting and as post-exposure
prophylaxis.
Terima Kasih…..