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.
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.
Drug: Tocilizumab
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 Name: Actemra
Drug: Placebos
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)
Inclusion criteria:
Subjects who meet all of the following criteria will be eligible to participate in the
study:
1. Must have provided informed consent in a manner approved by the Investigator's
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) prior to any
assessments. If a patient is unable to provide informed consent due to their medical
condition, the patient's legally authorized representative may consent on behalf of
the study patient, as permitted by local law and institutional Standard Operating
Procedures;
2. Age Range: 19-85 years old
3. Male or female gender
4. Confirmed SARS-CoV-2 infection by nasopharyngeal swab PCR or serum assay for IgM
antibody
5. Requiring hospital but not mechanical ventilation
6. Oxygen supplementation not greater than 10L delivered by any device
7. WITH evidence of severe COVID-19 (at least 2 of the following):
1. Fever > 38C within 72 hours
2. Pulmonary infiltrate on CXR
3. Need for supplemental O2 to maintain saturation > 92%
8. AND at least 1 of the following:
1. Ferritin > 500 ng/ml
2. CRP > 50 mg/L
3. LDH >250 U/L
4. D-dimer > 1000 ng/mL
9. Women of childbearing potential (ie, not post-menopausal or surgically sterilized)
must have a negative highly sensitive urine or serum pregnancy test before
randomization. Participating women of childbearing potential must be willing to
consistently use effective methods of contraception (ie, condom, combined oral
contraceptive, implant, injectable, indwelling intrauterine device, or a vasectomized
partner) from screening until at least 90 days after administration of the last dose
of study drug;
10. The subject must be willing and able to provide informed consent and abide all study
requirements and restrictions.
Exclusion criteria:
Subjects who meet any of the following criteria will be excluded from participation in the
study:
1. Unable to provide verbal informed consent or have verbal agreement to participate
through attestation and signature of a Witness required, as outlined in the Partners
IRB's Table for Consenting in COVID Research that is More than Minimal Risk.
2. Subjects between the ages of 79 and 86 will be excluded if they have NYHA Class III/IV
heart failure, insulin-dependent diabetes mellitus, angina, or treatment of a
malignancy (excluding non-melanoma skin cancer) within six months
3. Uncontrolled bacterial, fungal, or non-COVID viral infection
4. Active TB
5. Any prior investigational immunosuppressive therapy within 28-days or 3 half-lives of
the agent (for instance with biologic or JAK inhibitor)
6. Any concurrent immunosuppressive medication that the PI believes would put the patient
at higher risk
7. Receipt of intravenous tocilizumab for the treatment of a non-COVID condition within
three weeks of the first COVID symptom
8. History of hypersensitivity to tocilizumab
9. Any concurrent immunosuppressive medication that the PI believes would put the patient
at higher risk
10. Treatment with other biologic or small-molecule immunosuppressive therapy such as
IL1R-antagonism, JAK inhibition, or other agents
11. Treatment with convalescent plasma
12. History of diverticulitis or bowel perforation
13. ANC <500, Platelets <50,000*
14. AST/ALT > 5X ULN
15. Women who are pregnant or planning to get pregnant in the next 90 days;
16. Any condition that could interfere with, or for Known allergy to the study drug or any
of its ingredients or known allergy to any other anti IL 6 agents;
17. Any condition that could interfere with or for which the treatment might interfere
with, the conduct of the study or interpretation of the study results, or that would,
in the opinion of the Investigator, increase the risk of the subject by participating
in the study.
We note that anti-viral therapies may be administered to subjects if given in the context
of a clinical trial. Nitric oxide treatment is also permitted at the discretion of the care
team, ideally in the context of a clinical trial. Co-treatment chloroquine,
hydroxychloroquine, and/or azithromycin is permitted for subjects in this protocol.
Massachusetts General Hospital
Boston, Massachusetts, United States
Brigham and Women's Hospital
Boston, Massachusetts, United States
Newton-Wellesley Hospital
Newton, Massachusetts, United States
John H Stone, MD, Principal Investigator
Massachusetts General Hospital