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Efficacy of Tocilizumab on Patients With COVID-19

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04356937
Recruitment Status : Not yet recruiting
First Posted : April 22, 2020
Last Update Posted : April 22, 2020
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Stone, John H, M.D., M.P.H, Massachusetts General Hospital

Brief 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.

Participants will complete screening procedures, where inclusion and exclusion criteria will be evaluated. After screening, participants who meet all inclusion criteria and none of the exclusion criteria will be randomized 2:1 to tocilizumab or placebo. Participants will be followed for safety for 28 days after the last dose of study drug.

We anticipate enrolling between 300 patients admitted to Massachusetts General Hospital (and additional Partners sites, after approval, including BWH, NSMC, and the NWH) into the trial.


Condition or disease Intervention/treatment Phase
SARS-CoV 2 Drug: Tocilizumab Drug: Placebos Phase 3

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%. 1,2 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.3,4 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.4 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).3 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.5 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.6 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.5,7,8 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.9 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. We propose a trial of IL-6 receptor blockade with tocilizumab given early in disease course to try to prevent progression of COVID-19.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Prospective, single-center, placebo-controlled, blinded, randomized controlled trial at MGH
Masking: Double (Participant, Investigator)
Masking Description: participants who meet all inclusion criteria and none of the exclusion criteria will be randomized 2:1 to tocilizumab or placebo.
Primary Purpose: Treatment
Official Title: Tocilizumab to Prevent the Progression of Hypoxemic Respiratory Failure in Hospitalized Non-Critically Ill Patients With COVID-19
Estimated Study Start Date : April 27, 2020
Estimated Primary Completion Date : June 30, 2020
Estimated Study Completion Date : August 30, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Tocilizumab

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:

  1. Tocilizumab 8mg x 1 (n=185)
  2. Standard of care/Placebo (n=93)
Other Name: Actemra

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: 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:

  1. Tocilizumab 8mg x 1 (n=185)
  2. Standard of care/Placebo (n=93)




Primary Outcome Measures :
  1. Proportion of patients that require mechanical ventilation [ Time Frame: 28 days ]
    tocilizumab can decrease progression of COVID-19 associated respiratory failure necessitating ICU admission.


Secondary Outcome Measures :
  1. Requirement for inotropes and/or vasopressors [ Time Frame: 28 days ]
  2. 8-level Clinical improvement Scale [ Time Frame: 28 days ]
    Assessed at day 7, 14, 28 or day of discharge.Defined as moving up 2 levels on the following scale

  3. Duration of mechanical ventalition [ Time Frame: 28 days ]
  4. Hospital discharge [ Time Frame: 28 days ]
    Time to hospital discharge

  5. Mortality [ Time Frame: 28 days ]
    Mortality at day 7, 14 and 28

  6. Duration of ICU stay [ Time Frame: 28 days ]
    Duration of ICU stay (up to Day 28)

  7. Duration of time on supplemental oxygen [ Time Frame: 28 days ]
  8. The proportion of patients who require renal replacement therapy or have doubling of creatinine [ Time Frame: 28 days ]
    The proportion of patients who require renal replacement therapy or have doubling of creatinine from baseline at Day 14 and Day 28



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Patients 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 > 18 and < 80 years old
  3. Male or female gender
  4. Confirmed SARS-CoV-2 infection by NP swab PCR
  5. Admitted to non-ICU level care at MGH
  6. WITH evidence of severe COVID-19 (at least 1 of the following):

    1. Fever > 38C
    2. Bilateral pulmonary infiltrates on chest X ray
    3. Need for supplemental O2 to maintain saturation > 92%
  7. AND at least 1 of the following:

    1. Ferritin > 500 ng/ml
    2. CRP > 50 mg/L
  8. 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;
  9. The patient must be willing and able to provide informed consent and abide all study requirements and restrictions.

Exclusion criteria:

Patients who meet any of the following criteria will be excluded from participation in the study:

  1. Unable to provide verbal informed consent
  2. Uncontrolled bacterial, fungal, or non-COVID viral infection
  3. Active TB or LTBI with < 1 month of treatment
  4. Any prior investigational immunologic therapy (for instance with biologic or JAK inhibitor) within 28-days or 3 half-lives of the agent
  5. Any concurrent immunosuppressive medication that the PI believes would put the patient at higher risk
  6. Oral or IV corticosteroid for non-COVID-19 indication within the last 7 days at a dose of ≥ 10 mg prednisone or equivalent per day
  7. History of diverticulitis or bowel perforation
  8. ANC <500, Platelets <50,000*
  9. AST/ALT > 5X ULN
  10. Women who are pregnant or planning to get pregnant in the next 90 days;
  11. 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;
  12. 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 participant by participating in the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04356937


Contacts
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Contact: John H Stone, MD,MPH 6177267938 JHSTONE@mgh.harvard.edu
Contact: Ana D Fernandes, MA 617-643-2140 adfernandes@mgh.harvard.edu

Locations
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United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Sponsors and Collaborators
Massachusetts General Hospital
Genentech, Inc.
Investigators
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Principal Investigator: John H Stone, MD Massachusetts General Hospital
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Responsible Party: Stone, John H, M.D., M.P.H, Principal Investigator, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT04356937    
Other Study ID Numbers: 2020P001159
First Posted: April 22, 2020    Key Record Dates
Last Update Posted: April 22, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Request for IPD can be submitted to PI for review

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No