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]