None listed
Conditions
Brief summary
Severe SARS-CoV-2 infection requiring intensive care unit (ICU) admission is associated with a high mortality driven mainly by development of acute respiratory distress syndrome (ARDS) and massive cytokine release. Tocilizumab (TCZ) is an anti-human IL-6 receptor monoclonal antibody that inhibits signal transduction by binding soluble IL-6 receptors (sIL-6R) and membrane bound IL-6 receptors (mIL-6R) and is currently approved for rheumatoid arthritis and cytokine release syndrome in response to chimeric antigen receptor T cell (CAR-T) therapies. Initial reports have shown that TCZ may be effective in the treatment of critically ill patients with coronavirus disease 2019 (COVID-19). This study will be an open label, multi-centre, parallel group, randomised controlled trial to determine if TCZ treatment in addition to standard care within the ICU results in improved clinical outcomes compared to standard care alone.
Interventions
Patients with confirmed severe SARS-CoV-2 infection will be screened and those that meet eligibility criteria, and who consented (or whose next of kin or guardian consent will be enrolled in the study. Patients will be randomized 2:1 on Day 1 to receive a single dose of 400 mg TCZ (Actemra®, Roche Products Pty Limited) administered intravenously over 1 h (in addition to standard of care), or standard of care alone.
Standard of care will be determined by the treating clinician for each individu
Patients with confirmed severe SARS-CoV-2 infection will be screened and those that meet eligibility criteria, and who consented (or whose next of kin or guardian consent will be enrolled in the study. Patients will be randomized 2:1 on Day 1 to receive a single dose of 400 mg TCZ (Actemra®, Roche Products Pty Limited) administered intravenously over 1 h (in addition to standard of care), or standard of care alone. Standard of care will be determined by the treating clinician for each individual patient and will be in accordance with the evolving treatment guidelines for critically ill patients with COVID-19. Treatments may include antiviral agents (e.g. LPV/r, HCQ), or antibiotics (use adjunctive therapies such as steroids is discouraged but will be allowed if deemed necessary). Adherance to the intervention will be recorded in product accountability log and source data verification. Clinical data collection (ICU interventions including drug treatments, vital signs, adverse events) and safety blood sampling will be performed daily until day 29, ICU discharge, or death, whichever is earlier. If the participant is discharged from ICU but remains hospitalised, data will be collected daily until day 8 and also on Days 15 and Day 29. If the patient is discharged prior to Day 15 or Day 29, then a phone call will be made to ascertain clinical status. Blood sampling for immunological analyses, and chest imaging, will be performed at baseline and select timepoints during the study. We hypothesise that TCZ treatment in conjunction with standard of care will lead to a reduction in the number of days patients admitted to the ICU with severe SARS-CoV-2 infection require ventilatory support, compared with standard of care alone. A total of 150 patients are planned to be enrolled in the study (100 patients in the intervention group and 50 patients in the control group). This is an open-ended study given the uncertainties of the epidemiological course of SARS-CoV-2. The Data and Safety Monitoring Board (DSMB) will perform several interim analyses during the study
Sponsors
QIMR Berghofer Medical Research Institute
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female aged greater than or equal to 18 years 2. Confirmed SARS-CoV-2 by PCR with sample taken within 14 days prior to randomisation 3. Requirement for invasive or non-invasive ventilatory support or admission to ICU (or planned commencement of invasive or non-invasive ventilatory support, or planned admission to ICU) 4. Enrolled prior to or within 24 hours of ICU admission
Exclusion criteria
1. Absolute neutrophil count less than 0.5x10e9/Litre, platelets less than 50x10e9/Litre 2. Previous TNF alpha antagonist treatment within the last 3 months 3. Confirmed bacterial sepsis or untreated bacterial, mycobacterial or fungal infection 4. Untreated hepatitis B virus infection 5. Recent major surgery within the last 8 weeks 6. Organ transplant recipients 7. Primary or secondary immunodeficiency 8. History of diverticulitis, inflammatory bowel disease, or other symptomatic gastrointestinal condition that might predispose to bowel perforation 9. Known cirrhosis or aminotransferases greater than 5 times upper limit of normal 10. Pregnant or breastfeeding 11. Known allergy or hypersensitivity to TCZ or other monoclonal antibodies 12. Previous participation in the trial 13. Patient being treated with palliative intent, or not expected to be alive in 48 hours
Outcome results
None listed