Clinical trial NCT04356937: Efficacy of Tocilizumab on Patients With COVID-19
Official title: Tocilizumab to Prevent the Progression of Hypoxemic Respiratory Failure in Hospitalized Non-Critically Ill Patients With COVID-19
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: SARS-CoV 2
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
First posted: 2020-04-22
Enrollment: 243
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, multi-center, randomized,double blind, placebo-controlled trial
Primary purpose: TREATMENT

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.

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.

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.

Primary outcomes:
measure: Mechanical Ventilation or Death
timeFrame: 28 days
Secondary outcomes:
measure: Clinical Worsening on Ordinal Scale
timeFrame: 28 days
measure: Discontinuation of Supplemental Oxygen Among Patients Receiving it at Baseline
timeFrame: 28 days
Other outcomes:
measure: Duration of Supplemental Oxygen
timeFrame: 28 days
measure: Duration of Mechanical Ventilation
timeFrame: 28 days
measure: Mortality
timeFrame: 28 days
measure: ICU Admission or Death Among Those Not in the ICU at the Time of Administration of Investigational Agent (or Placebo)
timeFrame: 28 days
measure: Hospital Discharge
timeFrame: 28 days
measure: Clinical Improvement on Ordinal Scale
timeFrame: 28 days
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Newton
country: United States
facility: Newton-Wellesley Hospital
state: Massachusetts
Study officials:
affiliation: Massachusetts General Hospital
name: John H Stone, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Stone JH, Frigault MJ, Serling-Boyd NJ, Fernandes AD, Harvey L, Foulkes AS, Horick NK, Healy BC, Shah R, Bensaci AM, Woolley AE, Nikiforow S, Lin N, Sagar M, Schrager H, Huckins DS, Axelrod M, Pincus MD, Fleisher J, Sacks CA, Dougan M, North CM, Halvorsen YD, Thurber TK, Dagher Z, Scherer A, Wallwork RS, Kim AY, Schoenfeld S, Sen P, Neilan TG, Perugino CA, Unizony SH, Collier DS, Matza MA, Yinh JM, Bowman KA, Meyerowitz E, Zafar A, Drobni ZD, Bolster MB, Kohler M, D'Silva KM, Dau J, Lockwood MM, Cubbison C, Weber BN, Mansour MK; BACC Bay Tocilizumab Trial Investigators. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med. 2020 Dec 10;383(24):2333-2344. doi: 10.1056/NEJMoa2028836. Epub 2020 Oct 21.