Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial)

Abstract

Objective To investigate the effectiveness of using convalescent plasma to treat moderate coronavirus disease 2019 (covid-19) in adults in India. Design Open label, parallel arm, phase II, multicentre, randomised controlled trial. Setting 39 public and private hospitals across India. Participants 464 adults (≥18 years) admitted to hospital (screened 22 April to 14 July 2020) with confirmed moderate covid-19 (partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio between 200 mm Hg and 300 mm Hg or a respiratory rate of more than 24/min with oxygen saturation 93% or less on room air): 235 were assigned to convalescent plasma with best standard of care (intervention arm) and 229 to best standard of care only (control arm). Interventions Participants in the intervention arm received two doses of 200 mL convalescent plasma, transfused 24 hours apart. The presence and levels of neutralising antibodies were not measured a priori; stored samples were assayed at the end of the study. Main outcome measure Composite of progression to severe disease (PaO 2 /FiO 2 <100 mm Hg) or all cause mortality at 28 days post-enrolment. Results Progression to severe disease or all cause mortality at 28 days after enrolment occurred in 44 (19%) participants in the intervention arm and 41 (18%) in the control arm (risk difference 0.008 (95% confidence interval −0.062 to 0.078); risk ratio 1.04, 95% confidence interval 0.71 to 1.54). Conclusion Convalescent plasma was not associated with a reduction in progression to severe covid-19 or all cause mortality. This trial has high generalisability and approximates convalescent plasma use in real life settings with limited laboratory capacity. A priori measurement of neutralising antibody titres in donors and participants might further clarify the role of convalescent plasma in the management of covid-19. Trial registration Clinical Trial Registry of India CTRI/2020/04/024775.

LL-37 fights SARS-CoV-2: The Vitamin D-Inducible Peptide LL-37 Inhibits Binding of SARS-CoV-2 Spike Protein to its Cellular Receptor Angiotensin Converting Enzyme 2In Vitro

“…In contrast, LL-37 can be produced synthetically with high purity and in unlimited quantities. Also, the use of antibodies from reconvalescent donors did not result in clinical benefits or in reduction in all-cause mortality 47,48 . Therefore, the use of vitamin D as an infection prophylaxis and the therapeutic administration of vitamin D for the treatment of COVID-19 patients, and the direct use of LL-37 by inhalation or systemic application could be good alternatives.…”

How should we use convalescent plasma therapies for the management of COVID-19?

“…Agarwal and colleagues from India reported the PLACID RCT, where 464 hospitalized adults were randomized to receive either two doses of 200mL CP, with a median NAb titer of 1:40, given 24 hours apart, or control, in addition to standard care. 23 Participants who received CP did not show any improvement in the study's primary outcome (composite of progression to severe COVID-19 disease, or mortality at 28 days) compared to standard care. Detectable NAb at study entry were later detected in 80% of participants.…”

“…26 In the largest completed trial to date, the PLACID trial, NAb assays were not available at study commencement, and therefore not used to prospectively select CP. 23 Median NAb in CP administered across the trial was 1:40 (IQR 1:30-1:80), however only 68% of patients allocated to CP received plasma with detectable NAbs, and only 29% received CP with NAb >1:80. If future trials fail to show benefit, an important question will be whether this relates to insufficient antibody titer of the CP (due to low NAb titer and/or volume administered).…”

“…As the COVID-19 pandemic unfolded, 12 use of CP was described in early case reports and case series from China, Italy and elsewhere, to larger non-randomized studies, including through 'compassionate access' schemes and 'emergency use authorizations'. [13][14][15][16][17][18][19][20] Results of randomized controlled trials (RCTs) are now appearing [21][22][23][24][25][26] and 103 ongoing clinical trials are registered globally. See Figure 1 (to be prepared with ASH graphic designer).…”

“…Five RCTs have already been reported, although only three are published in the peer-reviewed literature and three were terminated early, mostly due to falling local case numbers. [21][22][23][24][25] See Table 2. Only one small trial 22 showed benefit from CP for a range of outcomes (including time to clinical recovery, progression to severe disease and mortality), although others reported benefits in secondary outcomes (e.g.…”