Efficacy of Tocilizumab on Patients With COVID-19
Condition: SARS-CoV 2
Intervention: Tocilizumab; Placebos
Intervention description: 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)
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Prospective, multi-center, randomized,double blind, placebo-controlled trial
Masking: Double (Participant, Investigator)
Masking description: Subjects who meet all inclusion criteria and none of the exclusion criteria will be randomized 2:1 to tocilizumab or placebo.
Enrollment: 243.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        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.