Anti-il6 Treatment of Serious COVID-19 Disease With Threatening Respiratory Failure (TOCIVID)

• ClinicalTrials.gov Identifier: NCT04322773
• Recruitment Status: Terminated
• First Posted: March 26, 2020
• Last Update Posted: October 9, 2020
• Sponsor: Marius Henriksen
• Information provided by (Responsible Party): Marius Henriksen, Frederiksberg University Hospital

Tracking Information

• First Submitted Date: March 24, 2020
• First Posted Date: March 26, 2020
• Last Update Posted Date: October 9, 2020
• Actual Study Start Date: April 5, 2020
• Actual Primary Completion Date: October 8, 2020 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: March 26, 2020): Time to independence from supplementary oxygen therapy [ Time Frame: days from enrolment up 28 days ]
• Original Primary Outcome Measures (submitted: March 24, 2020): Time to independence from supplementary oxygen therapy [ Time Frame: days from enrolment up 30 days ]

Current Secondary Outcome Measures (submitted: April 1, 2020)

• Number of deaths [ Time Frame: 28 days from enrolment ]
• Days out of hospital and alive [ Time Frame: 28 days from enrolment ]
• Ventilator free days alive and out of hospital [ Time Frame: 28 days from enrolment ]
• C-reactive protein (CRP) level [ Time Frame: baseline ]
  Measured from standard blood test
• C-reactive protein (CRP) level [ Time Frame: peak during hospitalisation, up to 28 days ]
  Measured from standard blood test
• C-reactive protein (CRP) level [ Time Frame: 14 days ]
  Measured from standard blood test
• C-reactive protein (CRP) level [ Time Frame: 28 days ]
  Measured from standard blood test
• Number of participants with serious adverse events [ Time Frame: During treatment, up to 28 days ]
  Measured as occurrence of any serious adverse events

Original Secondary Outcome Measures (submitted: March 24, 2020)

• Number of deaths [ Time Frame: 30 days from enrolment ]
• Days out of hospital and alive [ Time Frame: 30 days from enrolment ]
• Ventilator free days alive and out of hospital [ Time Frame: 30 days from enrolment ]
• C-reactive protein (CRP) level [ Time Frame: baseline ]
• C-reactive protein (CRP) level [ Time Frame: peak during hospitalisation, up to 30 days ]
• C-reactive protein (CRP) level [ Time Frame: 14 days ]
• C-reactive protein (CRP) level [ Time Frame: 30 days ]
• Number of participants with treatment-related side effects as assessed by Common Terminology Criteria for Adverse Event (CTCAE) [ Time Frame: During treatment, up to 30 days ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Anti-il6 Treatment of Serious COVID-19 Disease With Threatening Respiratory Failure
• Official Title: Effectiveness of Interleukin-6 Receptor Inhibitors in the Management of Patients With Severe SARS-CoV-2 Pneumonia: An Open-Label, Multicenter Sequential and Cluster Randomized Trial

Brief Summary

Coronavirus disease 2019 (COVID-19) is caused by the newly discovered coronavirus, SARS-CoV-2. The median time from onset of symptoms of COVID-19 to development of acute respiratory distress syndrome (ARDS) has been reported as short as 9 days. No effective prophylactic or post-exposure therapy is currently available. According to data from the Danish Health Authority (www.sst.dk/corona), as of March 21st, 2020, there were 1326 patients infected with the disease in Denmark, more than 250 are admitted to a hospital, and >50 of them have required intensive care. Nearly 350.000 cases and 15.000 deaths have been reported globally. These numbers are likely to markedly increase during the coming weeks, challenging the capacity of health systems worldwide.

In patients infected with SARS-CoV-2, it has been described that disease severity and outcomes are related to the characteristics of the immune response. Interleukin (IL)-6 and other components of the inflammatory cascade contribute to host defense against infections. However, exaggerated synthesis of IL-6 can lead to an acute severe systemic inflammatory response known as 'cytokine storm'. In the pathogenesis of SARS-CoV-2 pneumonia, a study found that a cytokine storm involving a considerable release of proinflammatory cytokines occurred, including IL-6, IL-12, and tumor necrosis factor α (TNF-α). Studies on the Middle East respiratory syndrome caused by another coronavirus (MERS-CoV), indicate that cytokine genes of IL-6, IL-1β, and IL-8 can be markedly upregulated. Similarly, patients with SARS-CoV-2 pneumonia admitted to an intensive care unit had higher plasma levels of cytokines including IL-6, IL-2, IL-7, IL-10, granulocyte-colony stimulating factor (G-CSF), interferon-γ-inducible protein (IP10), monocyte chemoattractant protein (MCP1), macrophage inflammatory protein 1 alpha (MIP1A), and TNF-α. These findings indicate that the magnitude and characteristics of the cytokine response is related to the severity and prognosis of patients with SARS-CoV-2 pneumonia.

It has been suggested that IL-6 blockade may constitute a novel therapeutic strategy for other types of cytokine storm, such as the systemic inflammatory response syndrome including sepsis, macrophage activation syndrome and hemophagocytic lymphohistiocytosis. Remarkable beneficial effects of IL-6 blockade therapy using a IL-6 receptor inhibitor has been described in patients with severe SARS-CoV-2 pneumonia in a retrospective case series from China.

Currently, there are two available drugs based on human monoclonal antibodies against IL-6 receptor, tocilizumab (RoActemra, Roche) and sarilumab (Kevzara, Sanofi). IL-6 receptor inhibitors are currently licensed for several autoimmune disorders and are considered well tolerated and safe in general. The most common side effects reported are upper respiratory tract infections, headache, hypertension, and abnormal liver function tests. The most serious side effects are serious infections, complications of diverticulitis, and hypersensitivity reactions.

it is hypothesized that IL-6 might play a key role in the cytokine storm associated with serious adverse outcomes in patients infected with SARS-CoV-2 pneumonia, and that blockade of IL-6 would be suitable therapeutic target for these patients. The study will investigate the effect of different types of IL-6 inhibition versus no adjuvant treatment compared to standard of care in patients with severe SARS-CoV-2 pneumonia.

Primary objective: To compare the effect of either one of three IL-6 inhibitor administrations, relative to the standard of care, on time to independence from supplementary oxygen therapy, measured in days from baseline to day 28, in patients with severe SARS-CoV-2 pneumonia.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Corona Virus Disease

Intervention

• Drug: RoActemra iv
  single dose treatment with tocilizumab 400 mg intravenously
  Other Name: tocilizumab 400 mg
• Drug: RoActemra sc
  single dose treatment with tocilizumab 2 x 162 mg subcutaneously
  Other Name: tocilizumab 2 x 162 mg
• Drug: Kevzara sc
  single dose treatment with sarilumab 1 x 200 mg subcutaneously
  Other Name: sarilumab 1 x 200 mg
• Other: Standard medical care
  management as usual

Study Arms

• Experimental: Roactemra iv
  Single dose treatment with 400 mg tocilizumab intravensously
  Interventions:

  • Drug: RoActemra iv
  • Other: Standard medical care
• Experimental: Roactemra sc
  Single dose treatment with 2 x 162 mg tocilizumab subcutaneously
  Interventions:

  • Drug: RoActemra sc
  • Other: Standard medical care
• Experimental: Kevzara sc
  Single dose treatment with 1 x 200 mg sarilumab subcutaneously
  Interventions:

  • Drug: Kevzara sc
  • Other: Standard medical care
• Active Comparator: Standard care
  Management as usual
  Intervention: Other: Standard medical care

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: October 8, 2020): 20
• Original Estimated Enrollment (submitted: March 24, 2020): 200
• Actual Study Completion Date: October 8, 2020
• Actual Primary Completion Date: October 8, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• SARS-CoV-2 infection confirmed by real time-PCR and
• Positive imaging: consolidation, ground glass opacities, or bilateral pulmonary infiltration either by CT-scan or chest x-ray; and
• Need of oxygen therapy to maintain SO2>94% OR FiO2/PaO2 > 20 and at least two of the following laboratory measures:
• CRP level >70 mg/L
• CRP level >= 40 mg/L and doubled within 48 hours (without other confirmed infectious or non-infectious course),
• Lactatdehydrogenase > 250 U/L,
• thrombocytopenia < 120.000 x 10E9/L,
• lymphocyte count < 0.6 x 10E9/L,
• D-dimer > 1 ug/mL,
• serum ferritin > 300 ug/mL

Exclusion Criteria:

• pregnancy suspected or confirmed,
• severe heart failure,
• suspected or confirmed bacterial infection,
• current solid or hematological malignancy,
• neutropenia,
• ALAT elevation more than three times the laboratory upper limit,
• ASA class 5 (after COVID19 admission) or higher at inclusion (prior admission),
• severe chronic obstructive pulmonary disease or heart failure (NYHA class II or higher),
• pregnant or lactating women,
• current treatment with conventional synthetic disease-modifying antirheumatic drugs (DMARDs)/immunosuppressive agents including IL-6 inhibitors, or with Janus kinase inhibitors (JAKi) in the past 30 days or plans to receive during the study period,
• current use of chronic oral corticosteroids in a dose higher than prednisone 10 mg or equivalent per day,
• previous or active tuberculosis (TB),
• HIV infection regardless of immunological status, hepatitis,
• evidence of recent (30 days) invasive bacterial or fungal infections,
• patients who have received immunosuppressive antibody therapy within the past 5 months, including intravenous immunoglobulin or plans to receive during the study period,
• IV drug abuse,
• history of inflammatory bowel disease,
• diverticulitis,
• ulcer,
• perforated gastrointestinal tract,
• participation in any clinical research study evaluating an investigational product (IP) or therapy within 3 months and less than five half-lives of IP prior inclusion to the study,
• any physical examination findings and/or history of any illness that, in the opinion of the study investigator, might confound the results of the study or pose an additional risk to the patient by their participation in the study,
• inability to give informed consent.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Denmark

Administrative Information

• NCT Number: NCT04322773
• Other Study ID Numbers: APPI2-CV-2020-01
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Yes
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Supporting Materials: Analytic Code

• Responsible Party: Marius Henriksen, Frederiksberg University Hospital
• Study Sponsor: Marius Henriksen
• Collaborators: Not Provided

Investigators

• Principal Investigator: Lars Erik Kristensen, PhD; The Parker Institute

• PRS Account: Frederiksberg University Hospital
• Verification Date: October 2020