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Trial registered on ANZCTR
Registration number
ACTRN12620000580976
Ethics application status
Approved
Date submitted
28/04/2020
Date registered
19/05/2020
Date last updated
23/08/2022
Date data sharing statement initially provided
19/05/2020
Type of registration
Prospectively registered
Titles & IDs
Public title
Tocilizumab for tReatment Of COVID-19 in intensive cARe patients (“TROCAR”)
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Scientific title
Tocilizumab for the treatment of COVID-19 in intensive care patients: effect on days free of ventilatory support.
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Secondary ID [1]
301036
0
none
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Universal Trial Number (UTN)
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Trial acronym
TROCAR
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
COVID-19
317089
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Condition category
Condition code
Infection
315254
315254
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0
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Studies of infection and infectious agents
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Respiratory
315397
315397
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0
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Other respiratory disorders / diseases
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
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
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Intervention code [1]
317345
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Treatment: Drugs
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Comparator / control treatment
Standard care therapy for COVID-19 patient admitted to Intensive Care Units
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Control group
Active
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Outcomes
Primary outcome [1]
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The number of days alive and free of ventilatory support as a composite outcome determined by data from patient records.
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Assessment method [1]
323497
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Timepoint [1]
323497
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up to day Day 29
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Secondary outcome [1]
382439
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Survival
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Assessment method [1]
382439
0
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Timepoint [1]
382439
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Daily up to day 29
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Secondary outcome [2]
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Number of patients with a reduction in pulmonary consolidation greater than 30 percent. This outcome will be assessed using chest imaging performed at screening and Day 6.
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Assessment method [2]
382440
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Timepoint [2]
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Day 6
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Secondary outcome [3]
382441
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Time to defervescence, defined as time taken for temperature to fall below 37.5 degrees Celsius and remain there for at least 48 hours. This outcome will be assessed using tympanic temperature and determined from medical records up to Day 29.
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Assessment method [3]
382441
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Timepoint [3]
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Daily until day 29
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Secondary outcome [4]
382442
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Time to clinical recovery, defined as time until there is no requirement for invasive or non-invasive ventilation or for supplemental oxygen. This outcome will be determined using data from patient records.
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Assessment method [4]
382442
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Timepoint [4]
382442
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days up to day 29
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Secondary outcome [5]
382443
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Number of antibiotic-free days This outcome will be determined using data from patient records.
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Assessment method [5]
382443
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Timepoint [5]
382443
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days up to day 15
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Secondary outcome [6]
382454
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Change from baseline in CRP, D-dimer and ferritin as a composite outcome. This outcome will be determined from laboratory assays using blood samples collected at baseline (Day 1), Day 3, Day 4, Day 8 and Day 29.
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Assessment method [6]
382454
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Timepoint [6]
382454
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baseline, days 3, 4, 8 and 29
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Secondary outcome [7]
382455
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Change from baseline in cytokines including IL-6, IL-1b, IL-10, IL-8, TNF, IL-12p70, IFNy, IL-17A, IL-4, MIP1a, MIP1b, MCP-1, CD178/FasL, granzyme B and RANTES as a composite outcome. This outcome will be determined from immunological assays that measure cytokines using blood samples collected at baseline (Day 1), Day 3, Day 8 and Day 29.
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Assessment method [7]
382455
0
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Timepoint [7]
382455
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Baseline, days 3, 8 and 29
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Secondary outcome [8]
382456
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Change from baseline in immune cell subsets, including anti-viral CD4+ and CD8+ T cells, activated T follicular helper (Tfh) cells, NK cells, dendritic cells and monocytes as a composite outcome. This outcome will be determined from flow cytometry and/or single cell transcriptomics assays using blood samples collected at Baseline (Day 1), Day 3, Day 8 and Day 29.
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Assessment method [8]
382456
0
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Timepoint [8]
382456
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baseline, day 3, 8 and 29
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Secondary outcome [9]
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Frequency of bacterial, mycobacterial, fungal infections from pathology results
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Assessment method [9]
382851
0
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Timepoint [9]
382851
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daily up to day 29
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Secondary outcome [10]
382852
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Frequency of cytopenias (neutrophil and platelet count drops) from blood tests
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Assessment method [10]
382852
0
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Timepoint [10]
382852
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daily up to day 29
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Secondary outcome [11]
382853
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Frequency of elevated liver transaminases (AST, ALT) from blood results
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Assessment method [11]
382853
0
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Timepoint [11]
382853
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daily up to day 29
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Secondary outcome [12]
382854
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Frequency of abnormal bleeding data from patient records
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Assessment method [12]
382854
0
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Timepoint [12]
382854
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Daily up to day 29
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Secondary outcome [13]
382855
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change from baseline in markers of endothelial activation, microvascular function and/or glycocalyx degradation, such as angiopoietin-2, osteoprotegerin, von-willebrand factor, syndecan-1, ICAM-1, E-selectin as a composite outcome. The outcome will be determined from laboratory assays using blood samples collected at Baseline (Day 1), Day 3, Day 8 and Day 29
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Assessment method [13]
382855
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Timepoint [13]
382855
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Baseline, Day 3, 8 and 29
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Eligibility
Key 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
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
To randomise the consented patient the site investigator or their delegate will log onto the data capture platform and enter the details required to obtain the treatment allocation assigned to that patient. The randomised sequence allocation will be done centrally and will be stored on the secure server of the data capture system.
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The patient will be assigned a randomisation number and group allocation. Compulsory fields required prior to randomisation are screening number, confirmation of eligibility, age, confirmation of consent from patient and treating team, and recruitment site.
Participants will be randomised in a 2:1 ratio to the intervention group or the control group. Randomisation will be in permuted blocks of variable block size.
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 1 / Phase 2
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Type of endpoint/s
Efficacy
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Statistical methods / analysis
Continuous variables will be summarised with the number of observations, mean, standard deviation, median, quartiles, minimum and maximum. Categorical variables will be summarised with the number of observations and the numbers and percent from each category.
Proportions will be compared between treatment groups with likelihood ratio chi square tests, and the absolute difference in proportions reported with corresponding 95 percent confidence intervals. All-cause survival will be presented in a Kaplan-Meier graph and compared with log-rank tests and observation is censored at 29 days. Ventilator-free days will be assessed to determine whether it is approximately normally distributed using quantile plots and transformed if necessary. Analysis will be via generalized regression or non-parametrics methods if deemed appropriate.
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Recruitment
Recruitment status
Withdrawn
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Reason for early stopping/withdrawal
Participant recruitment difficulties
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Date of first participant enrolment
Anticipated
19/10/2020
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Actual
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
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Sample size
Target
150
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
QLD
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Recruitment hospital [1]
16584
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Royal Brisbane & Womens Hospital - Herston
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Recruitment hospital [2]
16585
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Redcliffe Hospital - Redcliffe
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Recruitment hospital [3]
16586
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Mater Adult Hospital - South Brisbane
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Recruitment hospital [4]
16645
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The Prince Charles Hospital - Chermside
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Recruitment postcode(s) [1]
30173
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4029 - Herston
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Recruitment postcode(s) [2]
30174
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4020 - Redcliffe
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Recruitment postcode(s) [3]
30175
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4101 - South Brisbane
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Recruitment postcode(s) [4]
30241
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4032 - Chermside
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Funding & Sponsors
Funding source category [1]
305478
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Charities/Societies/Foundations
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Name [1]
305478
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QIMR Berghofer Medical Research Institute
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Address [1]
305478
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300 Herston Road
Herston
Brisbane, Queensland
4006
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Country [1]
305478
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Australia
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Primary sponsor type
Charities/Societies/Foundations
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Name
QIMR Berghofer Medical Research Institute
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Address
300 Herston Road
Herston
Brisbane, Queensland
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Country
Australia
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Secondary sponsor category [1]
305876
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None
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Name [1]
305876
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Address [1]
305876
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Country [1]
305876
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
305794
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Royal Brisbane and Women's Hospital HREC
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Ethics committee address [1]
305794
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Butterfield street
Herston
Brisbane, Queensland
4006
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Ethics committee country [1]
305794
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Australia
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Date submitted for ethics approval [1]
305794
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09/05/2020
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Approval date [1]
305794
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22/05/2020
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Ethics approval number [1]
305794
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HREC/2020/QRBW/63761
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Summary
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.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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A/Prof Bridget Barber
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Address
101618
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QIMR Berghofer Medical Research Institute
300 Herston Road
Herston QLD 4006,
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Country
101618
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Australia
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Phone
101618
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+61733620104
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Fax
101618
0
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Email
101618
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[email protected]
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Contact person for public queries
Name
101619
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A/Prof Bridget Barber
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Address
101619
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QIMR Berghofer Medical Research Institute
300 Herston Road
Herston QLD 4006,
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Country
101619
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Australia
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Phone
101619
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+61733620104
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Fax
101619
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Email
101619
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[email protected]
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Contact person for scientific queries
Name
101620
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A/Prof Bridget Barber
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Address
101620
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QIMR Berghofer Medical Research Institute
300 Herston Road
Herston QLD 4006,
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Country
101620
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Australia
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Phone
101620
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+61733620104
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Fax
101620
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Email
101620
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[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
Non available at this stage
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What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
Documents added manually
No documents have been uploaded by study researchers.
Documents added automatically
Source
Title
Year of Publication
DOI
Embase
Interleukin-6 blocking agents for treating COVID-19: a living systematic review.
2023
https://dx.doi.org/10.1002/14651858.CD013881.pub2
N.B. These documents automatically identified may not have been verified by the study sponsor.
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