Efficacy of Tocilizumab on Patients With COVID-19
Keywords
Abstract
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.
Dates
| Last Verified: | 06/30/2020 |
| First Submitted: | 04/18/2020 |
| Estimated Enrollment Submitted: | 04/18/2020 |
| First Posted: | 04/21/2020 |
| Last Update Submitted: | 07/01/2020 |
| Last Update Posted: | 07/06/2020 |
| Actual Study Start Date: | 04/19/2020 |
| Estimated Primary Completion Date: | 06/29/2020 |
| Estimated Study Completion Date: | 08/29/2020 |
Condition or disease
Intervention/treatment
Drug: Tocilizumab
Drug: Standard of care plus placebo
Phase
Arm Groups
| Arm | Intervention/treatment |
|---|---|
| Experimental: Tocilizumab Review effect of Tocilizumab on multi-organ dysfunction in a phase 3 randomized controlled trial among hospitalized patients with COVID-19 infection.
Participants will receive an intravenous (IV) injection of 8 mg/kg (not to exceed 800 mg) tocilizumab.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. | 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) |
| Placebo Comparator: Standard of care plus placebo Participants will receive an placebo intravenous (IV) injection of 8 mg/kg (not to exceed 800 mg).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. | Drug: Standard of care plus placebo 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) |
Eligibility Criteria
| Ages Eligible for Study | 18 Years To 18 Years |
| Sexes Eligible for Study | All |
| Accepts Healthy Volunteers | Yes |
| 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. |
Outcome
Primary Outcome Measures
1. Time to mechanical ventilation or death [28 days]
Secondary Outcome Measures
1. Time to improvement [28 days]
2. Time to progression to non-invasive ventilation or high-flow oxygen, defined as >6L [28 days]
3. Raw ordinal scale scores at days 4, 7, 14, 21, and 28. [Days 4, 7, 14, 21, and 28]
4. Time to absence of the need for supplemental oxygen [28 days]
5. Duration of supplemental oxygen [28 days]
6. Time to improvement in NEWS2 score to ≤ 2 or discharge from the hospital. [28 days]
7. Time to death [28 days]
8. Mortality at 28 days [28 days]
9. Time to intubation [28 days]
10. Duration of mechanical ventilation [28 days]
11. Proportion of subjects requiring ICU admission [28 days]
12. Time to discharge [28 days]
13. Safety and tolerability [28 days]
