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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
8/09/2020
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”)
Scientific title
Tocilizumab for the treatment of COVID-19 in intensive care patients: effect on days free of ventilatory support.
Secondary ID [1] 301036 0
none
Universal Trial Number (UTN)
Trial acronym
TROCAR
Linked study record

Health condition
Health condition(s) or problem(s) studied:
COVID-19 317089 0
Condition category
Condition code
Infection 315254 315254 0 0
Studies of infection and infectious agents
Respiratory 315397 315397 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
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
Intervention code [1] 317345 0
Treatment: Drugs
Comparator / control treatment
Standard care therapy for COVID-19 patient admitted to Intensive Care Units
Control group
Active

Outcomes
Primary outcome [1] 323497 0
The number of days alive and free of ventilatory support as a composite outcome determined by data from patient records.
Timepoint [1] 323497 0
up to day Day 29
Secondary outcome [1] 382439 0
Survival
Timepoint [1] 382439 0
Daily up to day 29
Secondary outcome [2] 382440 0
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.
Timepoint [2] 382440 0
Day 6
Secondary outcome [3] 382441 0
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.
Timepoint [3] 382441 0
Daily until day 29
Secondary outcome [4] 382442 0
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.
Timepoint [4] 382442 0
days up to day 29
Secondary outcome [5] 382443 0
Number of antibiotic-free days This outcome will be determined using data from patient records.
Timepoint [5] 382443 0
days up to day 15
Secondary outcome [6] 382454 0
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.
Timepoint [6] 382454 0
baseline, days 3, 4, 8 and 29
Secondary outcome [7] 382455 0
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.
Timepoint [7] 382455 0
Baseline, days 3, 8 and 29
Secondary outcome [8] 382456 0
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.
Timepoint [8] 382456 0
baseline, day 3, 8 and 29
Secondary outcome [9] 382851 0
Frequency of bacterial, mycobacterial, fungal infections from pathology results
Timepoint [9] 382851 0
daily up to day 29
Secondary outcome [10] 382852 0
Frequency of cytopenias (neutrophil and platelet count drops) from blood tests
Timepoint [10] 382852 0
daily up to day 29
Secondary outcome [11] 382853 0
Frequency of elevated liver transaminases (AST, ALT) from blood results
Timepoint [11] 382853 0
daily up to day 29
Secondary outcome [12] 382854 0
Frequency of abnormal bleeding data from patient records
Timepoint [12] 382854 0
Daily up to day 29
Secondary outcome [13] 382855 0
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
Timepoint [13] 382855 0
Baseline, Day 3, 8 and 29

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
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
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.
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.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Efficacy
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.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 16584 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [2] 16585 0
Redcliffe Hospital - Redcliffe
Recruitment hospital [3] 16586 0
Mater Adult Hospital - South Brisbane
Recruitment hospital [4] 16645 0
The Prince Charles Hospital - Chermside
Recruitment postcode(s) [1] 30174 0
4020 - Redcliffe
Recruitment postcode(s) [2] 30173 0
4029 - Herston
Recruitment postcode(s) [3] 30241 0
4032 - Chermside
Recruitment postcode(s) [4] 30175 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 305478 0
Charities/Societies/Foundations
Name [1] 305478 0
QIMR Berghofer Medical Research Institute
Address [1] 305478 0
300 Herston Road
Herston
Brisbane, Queensland
4006
Country [1] 305478 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
QIMR Berghofer Medical Research Institute
Address
300 Herston Road
Herston
Brisbane, Queensland
Country
Australia
Secondary sponsor category [1] 305876 0
None
Name [1] 305876 0
Address [1] 305876 0
Country [1] 305876 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305794 0
Royal Brisbane and Women's Hospital HREC
Ethics committee address [1] 305794 0
Butterfield street
Herston
Brisbane, Queensland
4006
Ethics committee country [1] 305794 0
Australia
Date submitted for ethics approval [1] 305794 0
09/05/2020
Approval date [1] 305794 0
22/05/2020
Ethics approval number [1] 305794 0
HREC/2020/QRBW/63761

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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 101618 0
A/Prof Bridget Barber
Address 101618 0
QIMR Berghofer Medical Research Institute
300 Herston Road
Herston QLD 4006,
Country 101618 0
Australia
Phone 101618 0
+61733620104
Fax 101618 0
Email 101618 0
bridget.barber@qimrberghofer.edu.au
Contact person for public queries
Name 101619 0
A/Prof Bridget Barber
Address 101619 0
QIMR Berghofer Medical Research Institute
300 Herston Road
Herston QLD 4006,
Country 101619 0
Australia
Phone 101619 0
+61733620104
Fax 101619 0
Email 101619 0
bridget.barber@qimrberghofer.edu.au
Contact person for scientific queries
Name 101620 0
A/Prof Bridget Barber
Address 101620 0
QIMR Berghofer Medical Research Institute
300 Herston Road
Herston QLD 4006,
Country 101620 0
Australia
Phone 101620 0
+61733620104
Fax 101620 0
Email 101620 0
bridget.barber@qimrberghofer.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Non available at this stage
What supporting documents are/will be available?
No other documents available
Summary results
No Results