Introduction
In December 2019, a novel coronavirus (severe acute respiratory syndrome
coronavirus 2, SARS-CoV-2) emerged in China and has since spread
globally. Nearly 20% of patients with coronavirus disease 2019
(COVID-19) experience hypoxaemia, which is the primary reason for
hospitalisation.[1] A significant proportion of patients admitted to
hospital for COVID-19 develop acute respiratory failure, with 12-24%
requiring intubation for invasive mechanical ventilation.[2-6]
The pathophysiology of COVID-19 associated lung injury is characterised
by diffuse alveolar damage, hyperinflammation, coagulopathy, DNA
neutrophil extracellular traps (NETS), hyaline membranes and
microvascular thrombosis.[7]
Our group and others have previously outlined the scientific rationale
for the use of nebulised unfractionated heparin (UFH) as a treatment for
COVID-19.[8, 9] Nebulised UFH has anti-viral, anti-inflammatory,
anticoagulant, and mucolytic effects. Our meta-trial of inhaled
nebulised UFH as a repurposed drug for COVID-19 adheres to the five core
principles and recommendations as described by the pharmacology
community in its ASCEPT-BPS statement as follows.[10] Firstly, UFH
has demonstrated antiviral activity in pre-clinical studies in
concentrations relevant for administration to humans. The SARS-CoV-2
Spike S1 protein receptor binding domain attaches to UFH and undergoes
conformational change that prevents it from binding to the Angiotensin
Converting Enzyme 2 (ACE-2) receptor.[11, 12] It was recently
demonstrated that spike protein binding to human epithelial cells
requires engagement of both cell surface heparan sulphate (HS) and
ACE-2, with HS acting as a co-receptor for ACE-2 interaction, and UFH
blocked the binding and infectivity of SARS-CoV-2 to human bronchial
epithelial cells.[13] The inhibition of SARS-CoV-2 infection of Vero
E6 cells by an UFH preparation was found to be concentration dependent,
occurred at therapeutically relevant concentrations and is significantly
stronger compared to low molecular weight heparins (LMWHs).[14]
Secondly, the optimal concentrations of UFH can be achieved for the
proposed mode of administration in the lungs (data on file in the
Investigator’s Brochure).
Thirdly, in our meta-trial we concurrently quantify in vivo dynamics and
time course of COVID-19. Specifically, we collect and report
patient-relevant clinical outcomes including rates of intubation, time
course of disease progression and mortality.
Fourthly, previous studies have provided information relevant to
posology optimisation for the immunomodulatory and anticoagulant effects
of inhaled nebulised UFH in acute lung injury and acute respiratory
distress syndrome, to ensure the appropriate intensity and timing of
therapy. Animal studies of nebulised UFH in different acute lung injury
models have consistently shown a positive effect on pulmonary
coagulation, inflammation and oxygenation.[8] Small human studies
indicate that nebulised UFH limits pulmonary fibrin deposition,
attenuates progression of acute lung injury and hastens recovery.[8]
Early-phase trials in patients with acute lung injury and related
conditions found that nebulised UFH reduced pulmonary dead space,
coagulation activation, microvascular thrombosis, improved lung injury
and increased time free of ventilatory support.[15-19] In a
pre-pandemic double-blind randomised study in 256 critically ill
ventilated patients, nebulised UFH limited progression of lung injury
including ARDS and accelerated return to home in survivors.[20] The
anti-inflammatory effects of inhaled UFH are thought to reduce pulmonary
hyperinflammation and the generation of DNA NETs, both of which
contribute to COVID-19 lung injury. The anticoagulant actions of
nebulised UFH limit fibrin deposition, hyaline membrane formation and
microvascular thrombosis, which are also important features of COVID-19.
Finally, our meta-trial is innovative, robustly designed, and combines
randomised controlled studies to determine efficacy and safety so that
the benefit-harm balance of inhaled nebulised UFH is identified. We
hypothesise that treatment with inhaled nebulised UFH of hospitalised
patients with COVID-19 limits progression to acute respiratory failure
requiring intubation, reduces the risk of death, reduces the risk of
clinical worsening, and improves oxygenation. The collective goal of the
proposed meta-trial is to reach a conclusion about the efficacy of
inhaled UFH in COVID-19 as quickly as possible by pooling information
from multiple clinical trials not originally configured as a
network.[21] This protocol and statistical analysis plan manuscript
has been prepared in accordance with the Standard Protocol Items:
Recommendations for Interventional Trials (SPIRIT) 2013 guideline and in
accordance with published guidelines for the content of statistical
analysis plans in clinical trials (Appendix 1 and 2).[22, 23]