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

NCT04322773 | Terminated Phase 2

• 1 other identifier: APPI2-CV-2020-01
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 2

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.

Conditions

Corona Virus Disease

Outcome Measures

Primary Outcomes (1)

• Time to independence from supplementary oxygen therapy

  days from enrolment up 28 days

Secondary Outcomes (8)

• Number of deaths

  28 days from enrolment

• Days out of hospital and alive

  28 days from enrolment

• Ventilator free days alive and out of hospital

  28 days from enrolment

• C-reactive protein (CRP) level

  baseline

• C-reactive protein (CRP) level

  peak during hospitalisation, up to 28 days

Study Arms (4)

Roactemra iv

EXPERIMENTAL

Single dose treatment with 400 mg tocilizumab intravensously

Drug: RoActemra iv; Other: Standard medical care

Roactemra sc

EXPERIMENTAL

Single dose treatment with 2 x 162 mg tocilizumab subcutaneously

Drug: RoActemra sc; Other: Standard medical care

Kevzara sc

EXPERIMENTAL

Single dose treatment with 1 x 200 mg sarilumab subcutaneously

Drug: Kevzara sc; Other: Standard medical care

Standard care

ACTIVE COMPARATOR

Management as usual

Other: Standard medical care

Interventions

RoActemra iv DRUG

single dose treatment with tocilizumab 400 mg intravenously

Also known as: tocilizumab 400 mg

Roactemra iv

RoActemra sc DRUG

single dose treatment with tocilizumab 2 x 162 mg subcutaneously

Also known as: tocilizumab 2 x 162 mg

Roactemra sc

Kevzara sc DRUG

single dose treatment with sarilumab 1 x 200 mg subcutaneously

Also known as: sarilumab 1 x 200 mg

Kevzara sc

Standard medical care OTHER

management as usual

Kevzara sc; Roactemra iv; Roactemra sc; Standard care

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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,
• 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,

Sponsors & Collaborators

• Marius Henriksen: lead

Study Sites (2)

Bispebjerg-Frederiksberg Hospital

Copenhagen, 2000, Denmark

Location

Hillerød Hospital

Hillerød, Denmark

Location

MeSH Terms

Interventions

tocilizumab

Study Officials

• Lars Erik Kristensen, PhD

  The Parker Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: March 24, 2020
• First Posted: March 26, 2020
• Study Start: April 5, 2020
• Primary Completion: October 8, 2020
• Study Completion: October 8, 2020
• Last Updated: October 9, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE

Locations

DK (2)