Inflammatory Signal Inhibitors for COVID-19 (MATIS)

COVID-19 pneumonia is characterised by respiratory and multi-organ failure in the context of marked systemic inflammation. It is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV2) infection. The hallmark of severe disease is hypoxia and a radiological pattern of acute lung injury that shares features with Acute Respiratory Distress Syndrome (ARDS). Early features of COVID-19 result from host viral response and typically include symptoms such as fever and dry cough. Later features, typically occurring beyond 7 days, are characterised by marked and progressive systemic inflammation, identified by elevations in a plethora of inflammatory molecules such as C-reactive protein, ferritin and IL6. In a subset of patients, hyperinflammatory responses drive acute lung injury and may result in catastrophic multi-organ failure and death.

The aetiology of COVID-19 induced ARDS is incompletely understood but appears to be associated with lung inflammation effected by a monocytic and neutrophilic infiltration, elevated cytokine levels and tissue damage. Elevations in circulating inflammatory molecules are associated with poor prognosis. In particular, the COVID-19 hyperinflammatory response syndrome is associated thrombotic complications which are postulated to drive cardiac dysfunction and microvascular thrombi, suggested by elevations in troponin and D-dimer, respectively. Similar hyperinflammatory responses are also seen in macrophage activation syndromes such as haemophagocytic lymphohistiocytosis, or in the cytokine release syndrome associated with chimeric antigen receptor T cell therapy. Further, preliminary data from China and Italy have shown immediate resolution of symptoms using anti-interleukin-6 agents (anti-IL6) therapy and Janus kinase inhibitors (JAK)/signal transducer and activator of transcription (STAT) inhibitors in patients with severe disease. There may be an early window of opportunity to treat the COVID-19 hyperinflammatory syndrome before acute lung injury leads to organ failure.

There are currently no approved treatments for COVID-19 pneumonia. This is a protocol for a randomised controlled, multi-arm trial of early intervention with inflammatory signal inhibitors.

Study purpose

A number of therapeutic interventions targeting inflammatory signalling might reduce the severity of the inflammatory response phase resulting in amelioration of the lung damage thereby averting respiratory failure and the need for mechanical ventilation. This trial aims to evaluate the efficacy of two inhibitors of key signalling pathways using drugs which are already licensed for use in other clinical indications.