Efficacy of Tocilizumab on Patients With COVID-19
Condition: SARS-CoV 2
Study type: Interventional
Phase: Phase 3

Summary: 
      This is a randomized, double blind, multi-center study to evaluate the effects of tocilizumab
      compared to placebo on patient outcomes in participants with confirmed SARS-CoV-2 infection
      and evidence of systemic inflammation.

      The aim of this study is to test the effect of Tocilizumab on multi-organ dysfunction in a
      phase 3 randomized controlled trial among hospitalized patients with COVID-19 infection.

      Specifically, as compared to placebo, we will test whether tocilizumab is associated with a
      reduction in multi-organ dysfunction among hospitalized COVID-19 adult patients with elevated
      inflammatory measures. Multi-organ dysfunction will be measured as the incidence of the
      following composite endpoint (mechanical ventilation, renal replacement therapy, mechanical
      support, need for inotropes or vasopressors, liver dysfunction (increased bilirubin), and
      all-cause mortality). We will also assess multiple pre-specified secondary (exploratory)
      endpoints and safety endpoints.

      We hypothesize that, as compared to placebo, tocilizumab will reduce transfer to the ICU,
      need for mechanical ventilation, increase rates of hospital discharge in patients diagnosed
      with severe COVID-19 infection and evidence of exaggerated inflammatory response.
    

Detailed description: 
      As of April 3, 2020, COVID-19 has been confirmed in over 1 million people worldwide, with an
      estimated symptomatic case fatality ratio of around 1.4%. Currently without an effective
      treatment for SARS-CoV-2 there is an urgent need for effective treatment to curtail the rate
      of respiratory failure, the leading cause of mortality in COVID-19 disease. Moreover, with
      increasing numbers of patients requiring intensive unit level care and mechanical
      ventilation, nations are already having to triage patients for ventilatory support due to
      limited resources and healthcare systems around the world being stretched to the point of
      collapse, highlighting the importance of identifying interventions that could prevent the
      development of respiratory failure for these patients.

      The disease course of COVID-19 includes an incubation period, an acute viral phase that most
      commonly presents with flu-like symptoms that in some individuals progresses to a severe
      hyperinflammatory phase marked by acute respiratory distress syndrome (ARDS) and hypoxemic
      respiratory failure.Though there is spectrum of clinical course, many progress to the
      hyperinflammatory phase around day seven of symptoms, often requiring intensive care unit
      (ICU) level care and mechanical ventilation. Accumulating evidence suggests that the
      pathophysiology underlying this profound decline is a severe inflammatory response as
      demonstrated by multi organ system dysfunction akin to cytokine release syndrome
      (CRS)/macrophage activation syndrome (MAS).CRS/MAS is a systemic hyperinflammatory syndrome
      on a spectrum with secondary hemophagocytic lymphohistiocytosis (sHLH), typically
      characterized by multiorgan failure that is often triggered by viral infections in the
      setting of excessive immune activation, typically with marked hyperferritinemia.Postmortem
      assessment of patients with COVID-19 have demonstrated pathologic findings consistent with
      MAS such as mono/lymphocytic infiltrates within the lung parenchyma with associated edema and
      alveolar congestion, splenic necrosis with macrophage proliferation and hemophagocytosis, as
      well as a lymphocyte/histiocyte predominate infiltrate of portal vasculature accompanying
      liver necrosis and sinusoidal congestion.Cytokine profiling of patients with MAS/sHLH
      overlaps with that seen in patients with severe COVID-19 and includes elevated levels of
      IL-1, IL-2, IL-7, IL-6, G-CSF, MCP- 1, and TNF-α as well as elevated D-dimer, C-reactive
      protein, LDH and troponins.Moreover, preliminary data from a non-randomized series of
      COVID-19 patients with "severe or critical COVID-19" from China who were treated with
      tocilizumab (in addition to standard therapies) showed they had dramatic improvement in
      fever, arterial oxygen saturation and inflammatory markers within the first 24-hours
      following administration.

      Taken together, these data strongly suggest an immunologic link between COVID-19 and immune
      dysregulation resulting in MAS. Clinical trials are already underway studying the role of
      immunomodulatory therapy including modulation of IL-1 and IL-6 and downstream pathways in the
      setting of CAR-T induced MAS (NCT04150913, NCT04071366) and agents such anakinra and
      tocilizumab have been used in this context with promising results and good safety profiles.
      There is an urgent and dire need to study the therapeutic role for immunomodulatory therapy
      in COVID-19 disease to both halt disease progression in patients at an individual level and
      prevent the inevitable saturation of healthcare resources at a systems level, to which end
      there are numerous ongoing international trials to expand these efforts into the setting of
      COVID-19 infection (ChiCTR2000029765, NCT04324021, TOCOVID-19). Based on the MGH experience
      thus far with COVID-19, including over 200 patients to date, the need for mechanical
      ventilation has been approximately 30%. With the upcoming surge anticipated between April
      17th and 21st we expect the need for hundreds of additional ICU beds. Investigators propose a
      trial of IL-6 receptor blockade with tocilizumab given early in disease course to try to
      prevent progression of COVID-19.
    

Intervention name(s): Tocilizumab; Placebos
Intervention type(s): Drug; Drug
Intervention description(s): Patients will receive the standard treatment for COVID-19 per MGH guidance and also be randomized (2:1) to one of the following arms:
Tocilizumab 8mg x 1 (n=185)
Standard of care/Placebo (n=93); Patients will receive the standard treatment for COVID-19 per MGH guidance and also be randomized (2:1) to one of the following arms:
Tocilizumab 8mg x 1 (n=185)
Standard of care/Placebo (n=93)
Other intervention name(s): Actemra
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Prospective, multi-center, randomized,double blind, placebo-controlled trial
Masking: Double (Participant, Investigator)
Primary purpose: Treatment