Corona Virus Disease Clinical Trial
Official title:
Effectiveness of Interleukin-6 Receptor Inhibitors in the Management of Patients With Severe SARS-CoV-2 Pneumonia: An Open-Label, Multicenter Sequential and Cluster Randomized Trial
Coronavirus disease 2019 (COVID-19) is caused by the newly discovered coronavirus,
SARS-CoV-2. The median time from onset of symptoms of COVID-19 to development of acute
respiratory distress syndrome (ARDS) has been reported as short as 9 days. No effective
prophylactic or post-exposure therapy is currently available. According to data from the
Danish Health Authority (www.sst.dk/corona), as of March 21st, 2020, there were 1326 patients
infected with the disease in Denmark, more than 250 are admitted to a hospital, and >50 of
them have required intensive care. Nearly 350.000 cases and 15.000 deaths have been reported
globally. These numbers are likely to markedly increase during the coming weeks, challenging
the capacity of health systems worldwide.
In patients infected with SARS-CoV-2, it has been described that disease severity and
outcomes are related to the characteristics of the immune response. Interleukin (IL)-6 and
other components of the inflammatory cascade contribute to host defense against infections.
However, exaggerated synthesis of IL-6 can lead to an acute severe systemic inflammatory
response known as 'cytokine storm'. In the pathogenesis of SARS-CoV-2 pneumonia, a study
found that a cytokine storm involving a considerable release of proinflammatory cytokines
occurred, including IL-6, IL-12, and tumor necrosis factor α (TNF-α). Studies on the Middle
East respiratory syndrome caused by another coronavirus (MERS-CoV), indicate that cytokine
genes of IL-6, IL-1β, and IL-8 can be markedly upregulated. Similarly, patients with
SARS-CoV-2 pneumonia admitted to an intensive care unit had higher plasma levels of cytokines
including IL-6, IL-2, IL-7, IL-10, granulocyte-colony stimulating factor (G-CSF),
interferon-γ-inducible protein (IP10), monocyte chemoattractant protein (MCP1), macrophage
inflammatory protein 1 alpha (MIP1A), and TNF-α. These findings indicate that the magnitude
and characteristics of the cytokine response is related to the severity and prognosis of
patients with SARS-CoV-2 pneumonia.
It has been suggested that IL-6 blockade may constitute a novel therapeutic strategy for
other types of cytokine storm, such as the systemic inflammatory response syndrome including
sepsis, macrophage activation syndrome and hemophagocytic lymphohistiocytosis. Remarkable
beneficial effects of IL-6 blockade therapy using a IL-6 receptor inhibitor has been
described in patients with severe SARS-CoV-2 pneumonia in a retrospective case series from
China.
Currently, there are two available drugs based on human monoclonal antibodies against IL-6
receptor, tocilizumab (RoActemra, Roche) and sarilumab (Kevzara, Sanofi). IL-6 receptor
inhibitors are currently licensed for several autoimmune disorders and are considered well
tolerated and safe in general. The most common side effects reported are upper respiratory
tract infections, headache, hypertension, and abnormal liver function tests. The most serious
side effects are serious infections, complications of diverticulitis, and hypersensitivity
reactions.
it is hypothesized that IL-6 might play a key role in the cytokine storm associated with
serious adverse outcomes in patients infected with SARS-CoV-2 pneumonia, and that blockade of
IL-6 would be suitable therapeutic target for these patients. The study will investigate the
effect of different types of IL-6 inhibition versus no adjuvant treatment compared to
standard of care in patients with severe SARS-CoV-2 pneumonia.
Primary objective: To compare the effect of either one of three IL-6 inhibitor
administrations, relative to the standard of care, on time to independence from supplementary
oxygen therapy, measured in days from baseline to day 28, in patients with severe SARS-CoV-2
pneumonia.
n/a
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