Clinical Trial of the Use of Anakinra in Cytokine Storm Syndrome Secondary to Covid-19. A Phase 2/3, Randomized, Open-label, Parallel Group, 2-arm, Multicenter Study Investigating the Efficacy and Safety of Intravenous Administrations of Anakinra, an Interleukin-1(IL-1) Receptor Antagonist, Added to Standard of Care, Versus Standard of Care, in Reducing Hyper-inflammation and Respiratory Distress in Patients With SARS- CoV-2 Infection

This protocol has been prepared by the Systemic Autoimmune Diseases Group (GEAS) steering committee from the Spanish Society of Internal Medicine (SEMI) in response to the current urgent situation that are living in Spain because of the COVID-19 pandemic. The GEAS member are experts in the treatment of autoinflammatory diseases and the use of biologic drugs in general, and anakinra in particular. importantly, in Spain, internal medicine physicians are currently involved in the treatment of patients infected with SARS-CoV-2.

The objective of this study is to investigate new possibilities to reduce the number of patients requiring mechanical ventilation. This is intended to address the most urgent need to preserve the access to intense care unit support to the lower possible number of patients and may potentially reduce mortality.

In December 2019, a respiratory condition caused by what was later identified as a new coronavirus (SARS-CoV-2) was detected in Wuhan Province, China. In these four months, the virus has spread throughout the world's population, in more than 100 countries and affecting thousands of people. The WHO declared in March that we were facing a pandemic because of this virus, in which Europe could now be considered the epicenter. The strict containment measures implemented in China, the mass detection of the virus with subsequent isolation of cases and contacts that has been carried out in countries such as Singapore, Taiwan or South Korea seem to have been useful in limiting the virus´ spread. Consequently, in our country, and given the extension of the infection, a state of alarm has been decreed, at least for four weeks. Despite the containment measures, numerous cases are still being diagnosed every day, with an approximate lethality of 3.7%, especially in those considered at risk such as patients over 60 years of age and with comorbidities (Report nº 17. COVID-19 situation in Spain on 27 March 2020. COVID-19 team. SiViES. CNE. CNM. ISCIII).

When SARS-CoV-2 infects the respiratory tract, it causes the disease called COVID-19. From the point of view of the natural evolution of the disease, this can be a mild respiratory syndrome, which will occur in approximately 80% of cases, or a more serious disease, with the appearance of pulmonary infiltrates and in some patients a respiratory distress with rapidly progressive worsening. This second phase, which is only reached by a subgroup of patients, is usually seen in the interval between day 7 and day 10 of the infection from the onset of symptoms. So far, there is no proven explanation for this great variability in its clinical expression.

The treatment used in our country so far is based on the combination of hydroxychloroquine, azithromycin and antiretrovirals (protease inhibitors, lopinavir), based on previous experiences. Several clinical trials are currently underway in Spain: PanCOVID-19 (Azithromycin + Hydroxychloroquine + lopinavir/ritonavir), GS-US-540-5774 (Remdesivir), EFC16844 (Sarilumab) and WA42380 (Tocilizumab) as well as international projects such as Discovery (NCT04315948), Solidarity and REMAP-CAP which include other treatment alternatives such as interferon-beta-1B or Anakinra.