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Efficacy of Tocilizumab on Patients With COVID-19

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ClinicalTrials.gov Identifier: NCT04356937
Recruitment Status : Completed
First Posted : April 22, 2020
Last Update Posted : December 16, 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.

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.


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%. 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 243 participants
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.
Primary Purpose: Treatment
Official Title: Tocilizumab to Prevent the Progression of Hypoxemic Respiratory Failure in Hospitalized Non-Critically Ill Patients With COVID-19
Actual Study Start Date : April 20, 2020
Actual Primary Completion Date : July 13, 2020
Actual Study Completion Date : August 27, 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. The primary endpoint is the time from administration of the investigational agent (or placebo) to requiring mechanical ventilation and intubation, or death for subjects who die prior to intubation [ Time Frame: 28 days ]
    The primary endpoint is the time from administration of the investigational agent (or placebo) to requiring mechanical ventilation and intubation, or death for subjects who die prior to intubation


Secondary Outcome Measures :
  1. Time from investigational medication (or placebo) to at least one point worsening on clinical improvement scale for subjects requiring supplemental oxygen (score >= 3) at baseline, or at least two point worsening otherwise (score = 2 at baseline [ Time Frame: 28 days ]

    Time to improvement will be assessed by changes in subjects' status, ranked on the ordinal scale:

    Clinical Improvement Scale

    1. Discharged (or "ready for discharge" as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or <= 2L supplemental oxygen)
    2. Non-ICU hospital ward (or "ready for hospital ward") not requiring supplemental oxygen
    3. Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen
    4. ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen
    5. ICU, requiring intubation and mechanical ventilation
    6. ICU, requiring ECMO or mechanical ventilation and additional organ support (e.g. vasopressors, renal replacement therapy)
    7. Death

    Higher scores indicate a worse outcome.


  2. Time from administration of the investigational agent (or placebo) to absence of the need for supplemental oxygen among those who require at least supplemental oxygen at baseline [ Time Frame: 28 days ]
    Time from administration of the investigational agent (or placebo) to absence of the need for supplemental oxygen among those who require at least supplemental oxygen at baseline


Other Outcome Measures:
  1. Time to first improvement from baseline of at least 2 points (or the maximum amount) on the ordinal scale given in Table 2. [ Time Frame: 28 days ]

    Time to improvement will be assessed by changes in subjects' status, ranked on the ordinal scale:

    Clinical Improvement Scale

    1. Discharged (or "ready for discharge" as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or <= 2L supplemental oxygen)
    2. Non-ICU hospital ward (or "ready for hospital ward") not requiring supplemental oxygen
    3. Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen
    4. ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen
    5. ICU, requiring intubation and mechanical ventilation
    6. ICU, requiring ECMO or mechanical ventilation and additional organ support (e.g. vasopressors, renal replacement therapy)
    7. Death

    Higher scores indicate a worse outcome.


  2. Time from initiation of supplemental oxygen to end of supplemental oxygen use during 28-day study follow-up period. [ Time Frame: 28 days ]

    Time to absence of the need for supplemental oxygen will be measured from time of investigational treatment administration. We will use the same approach as that employed for the comparison of time to clinical improvement. Only subjects on supplemental oxygen at the time of randomization will contribute to this analysis. Subjects who die will be censored at 29 days, and the groups will be compared using a stratified log-rank test and stratified Cox proportional hazards model.

    The duration of supplemental oxygen will be compared between the groups. For this analysis, we will include all subjects in the analysis by assigning all subjects who did not receive supplemental oxygen a value of 0. Subjects who died following supplemental oxygen will be given a value of the number of days from when supplemental oxygen began until the end of the follow-up period. The groups will be compared using a Wilcoxon rank sum test.


  3. Time from administration of the investigational agent (or placebo) to death [ Time Frame: 28 days ]
    Time to death will be measured from the time the investigational medication is administered until the time of the subject's death. We will compare the groups using a stratified log-rank test and estimate the hazard ratio comparing the groups using a stratified Cox proportional hazards model.

  4. Time from administration of the investigational medication (or placebo) to intubation. [ Time Frame: 28 days ]
    Time to intubation will be measured from time of investigational treatment administration to the time of intubation. For this analysis, death will be treated as a competing risk. The analysis will compare the cause-specific hazard in the treatment groups using a Cox proportional hazards model. We will also compare the cumulative incidence functions between groups using the approach of Fine and Gray.

  5. Mortality at 28 days after administration of investigational agent (or placebo). [ Time Frame: 28 days ]
    Mortality at 28 days will be compared using a Mantel-Haenszel test to allow stratification on study site. The relative risk will be estimated using the Mantel-Haenszel method. If we have missing mortality data on any subjects, we will estimate the proportion of subjects who died in each treatment group using the estimate from the Kaplan-Meier curve in each group. Then, we will compare the two groups using the approaches described in Klein et al (citation: Klein JP, Logan B, Harhoff M, Anderson PK. Analyzing survival curves at a fixed point in time. Statistics in Medicine. 2007;26:4505-4519.)

  6. Duration of mechanical ventilation during 28-day study follow-up period. [ Time Frame: 28 days ]
    The duration of mechanical ventilation will be compared between the groups using two approaches. First, we will include all subjects in the analysis by assigning all subjects who were not intubated a value of 0. Subjects who died following intubation will be given a value of the number of days from when mechanical ventilation began until the end of the follow-up period. The groups will be compared using a Wilcoxon rank sum test. Second, we will analyze only subjects who were intubated and compare the time on mechanical ventilation using a stratified log-rank test. Subjects who die without being taken off the ventilator will be censored at a duration of mechanical ventilation longer than the longest time.

  7. ICU admission or death among those not in the ICU at the time of administration of investigational agent (or placebo). [ Time Frame: 28 days ]
    The proportion of subjects requiring ICU admission between baseline and 28 days will be measured as the number of subjects requiring ICU admission over their hospitalization over the number of evaluable subjects (i.e., the number of subjects not in the ICU at the time of investigational treatment administration). The groups will be compared using a Mantel-Haenszel test to allow stratification on study site. The relative risk will be estimated using the Mantel-Haenszel method.

  8. Time from administration of the investigational medication (or placebo) to hospital discharge [ Time Frame: 28 days ]
    The time to discharge from the hospital in subjects, measured from the time of investigational treatment administration to time of discharge, will be compared using a stratified log-rank test. Subjects who die will be censored at Day 29 to indicate that they never left the hospital during the study.

  9. Safety and tolerability [ Time Frame: 28 days ]
    The proportion of adverse events graded by CTCAE v5.0

  10. Ordinal Clinical Improvement Scale (Table 2) score at day: 4, 7, 14, 21, and 28. [ Time Frame: Days 4, 7, 14, 21, and 28 ]
    The raw ordinal scale scores at days 4, 7, 14, 21, and 28 in subjects treated with tocilizumab therapy versus controls will be compared at each time point using a random intercept proportional odds logistic regression model. This model will be used to model all measurements together to estimate the differences between the treatment groups at each time point.



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 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


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


Locations
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United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Newton-Wellesley Hospital
Newton, Massachusetts, United States, 02462
Sponsors and Collaborators
Massachusetts General Hospital
Genentech, Inc.
Investigators
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Principal Investigator: John H Stone, MD Massachusetts General Hospital
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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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: December 16, 2020
Last Verified: December 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