Clinical Trial of the Use of Anakinra in Cytokine Storm Syndrome Secondary to Covid-19 (ANA-COVID-GEAS)
Condition: COVID-19 Pnemonia
MeSH terms: COVID-19; Cytokine Release Syndrome
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Phase 2/3 randomized, parallel group, 2-arm study (treatment vs. control), investigating the
      efficacy and safety of intravenous administration of anakinra, an interleukin 1 receptor
      antagonist ( IL-1), added to standard treatment, compared to standard treatment alone, to
      reduce hyperinflammation and respiratory distress in patients with SARS-CoV-2 infection.
    

Detailed description: 
      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.

      According to recent data from the Chinese cohorts, a subgroup of patients with COVID-19 shows
      a very marked increase in inflammatory test data, such as lymphopenia, thrombocytopenia,
      C-reactive protein (CRP) levels, lactate dehydrogenase (LDH), IL6 (> 40 pg / mL) and D-dimer
      (> 0.28 μg / L), the latter two being predictive of the development of severe pneumonia
      (sensitivity 93.3%, specificity 96.4%). Accumulating evidence suggests that a subgroup of
      patients with severe COVID-19 might have a cytokine storm syndrome (CSS). In this group of
      patients in which this "inflammatory profile" is detected, the damage observed is not a
      direct consequence of the viral infection (viral necrotizing pneumonia) but rather a
      secondary hyperimmune response, mainly related to the monocyte/macrophage activation, which
      has also been observed in autopsy studies and previously in other infections by other types
      of coronavirus. This CSS is superimoosable to that observed in patients with secondary
      hemophagocytic lymphohistiocytosis (sHLH), often triggered by viral infections or macrophage
      activation syndrome (MAS), secondary to systemic and autoinflammatory autoimmune diseases.

      In this group of patients there is a significant release of pro-inflammatory cytokines,
      including interleukin (IL) -1β and IL-6. Of these, IL-1β has a greater pathogenic relevance,
      given that it promotes the inflammatory cascade and also induces the synthesis of several
      inflammatory genes such as IL-6 itself, IL-8, MCP-1, COX-2, IκBα, IL-1α, IL-1β and MKP-1.
      Numerous case reports and case series have been published supporting the use of IL-1β
      blockade in the MAS. At this time, there is some experience in the treatment of COVID-19 in
      the subgroup of patients in the inflammatory phase with Tocilizumab (IL-6 receptor blocker),
      but no controlled studies have been completed as yet. However, IL-6 is not a key molecule in
      the cytokine storm that triggers MAS.

      Anakinra (IL-1Ra) is a recombinant IL-1 receptor antagonist with a very short half-life of
      4-6 hours, requiring a daily subcutaneous injection of a 100 mg dose. It has also been shown
      to reduce levels of other pro-inflammatory cytokines (including IL-6 and IL-18) and acute
      phase reactants such as PCR and ferritin. Therefore, it has been used in the control of
      autoinflammatory syndromes and in patients with MAS. In addition, data have been reported
      from a phase 3 randomized controlled trial of IL-1 blockade with anakinra in sepsis with
      characteristics of MAS, which showed a significant improvement in the 28-day survival rate
      (65.4% anakinra vs. 35.3% placebo), with HR for death 0.28 (0.11-0.71, p = 0.0071), with no
      increased adverse events.

      As shown by the data available in the most recent literature generated from the Chinese
      experience, and by the most recent data made available by the different Spanish hospitals
      responsible for the management of these patients, hyper- inflammation, caused by a cytokine
      storm resulting from an exaggerated response of the immune system to the presence of the
      virus (CSS-like pneumonia), is considered to represent one of the most important negative
      prognostic factor in patients infected with SARS-CoV-2. The inclusion criteria for COVID-19
      used in this protocol is based on the analysis of routine blood chemistry data obtained from
      patients with SARS-CoV-2 infection. This criterion has been designed with high sensitivity
      (>90%) for patients who require ICU admission. This constitute the rationale for testing
      drugs specifically targeted to reduce the cytokine storm.

      This protocol has been prepared for the purpose of addressing the current medical emergency,
      given the severity of the disease and the extremely high number of individuals affected. The
      objective of this study is to investigate anakinra 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.

      The potential applicability of the results of this clinical trial, in an extraordinary health
      emergency such as COVID-19, is obvious. Positive results could help to define the standard
      treatment of severe COVID-19 pneumonia and have a dramatic impact on both local and global
      morbidity and mortality. Negative results would constitute very useful scientific evidence
      for abandoning unfounded empirical approaches and would help redirect resources and efforts
      in another more promising direction. The expected length of time needed for recruitment is
      3-4 weeks, depending on the epidemiological progression of the pandemic in our centers, so
      results could be available in early May 2020.

      Anakinra is a recombinant form of the human IL-Ra, r-metHuIL-1Ra, which is produced by
      recombinant DNA technology in an E. coli expression system. Therapeutically, anakinra
      neutralizes the biological activity of IL-1 (IL-1α and IL-1β) by competitively inhibiting its
      binding to the IL-1RI.

      Kineret (anakinra) was first approved for treatment of RA in the US in 2001 and subsequently
      in the EU/EEA in 2002. In 2012, an sBLA on anakinra for treatment of NOMID was approved in
      the US. Kineret is also approved for treatment of CAPS (in EU/EEA, Israel and Australia),
      Still's disease, including SJIA and AOSD (in EU/EEA) and SJIA (in Australia).

      The initial IND for anakinra was granted in 1991. The estimated cumulative exposure to
      anakinra in completed company sponsored clinical studies up to 1 May 2018 is 6404 subject-
      years, in 8518 subjects with various indications. Anakinra is administered s.c. at doses of
      100 mg/day (RA) or in weight-based doses of up to 8 mg/kg/day (NOMID). In clinical studies in
      sepsis, doses up to 2 mg/kg/hour i.v. over 72 hours were administered to >500 patients and
      were well tolerated.
    

Intervention name(s): Anakinra 149 MG/ML Prefilled Syringe [Kineret]
Intervention type(s): Drug
Intervention description(s): Anakinra (100 mg/ 6 hours) i.v infusión during 15 days
Intervention MeSH terms: Interleukin 1 Receptor Antagonist Protein
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: A phase 2/3, randomized, open label, parallel group, 2-arm, multicenter study investigating the efficacy and safety of intravenous administrations of the study drug,
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Covid-19 disease; pneumonia; Cytokine Storm Sindrome; Anti IL-1; Anakinra