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Trial registered on ANZCTR


Registration number
ACTRN12620000844943
Ethics application status
Approved
Date submitted
20/08/2020
Date registered
26/08/2020
Date last updated
26/08/2020
Date data sharing statement initially provided
26/08/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
C-SMART.
COVID-19 Prevention and Treatment in Cancer
Arm 4: treatment among cancer patients with severe COVID-19 infection.
Scientific title
COVID-19 Prevention and Treatment in Cancer; a Sequential Multiple Assignment Randomised Trial; C-SMART study
Arm 4: Effect of Lenzilumab in cancer patients with severe COVID-19 infection.
Secondary ID [1] 302087 0
nil known
Universal Trial Number (UTN)
U1111-1256-8488
Trial acronym
C-SMART (Arm 4)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
COVID-19 318698 0
Cancer 318699 0
Condition category
Condition code
Infection 316712 316712 0 0
Other infectious diseases
Cancer 316713 316713 0 0
Any cancer
Respiratory 316777 316777 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
ARM 4 - Severe COVID-19 infection
Drug: Lenzilumab
Dose: 600mg 8 hourly
Duration: 24 hours
Mode: Intravenous - administered by nurse.
adherence: inpatient records

Description of study design:
This SMART design specifies that participants entering the trial who have had no known COVID-19 exposure are initially randomised to either low-dose intranasal IFN-a or placebo as pre-exposure prophylaxis against developing COVID-19. Any participants who have a known COVID-19 exposure are randomised to high-dose IFN-a or placebo as a post-exposure prophylaxis against developing COVID-19. If, at any stage after enrolling, a participant develops ‘moderate’ COVID-19, then they are then randomised to either selinexor or placebo, and if at any stage after enrolling the participant develops ‘severe’ COVID-19 they are then randomised to either lenzilumab or placebo.
Importantly, participants enrolling into the trial can directly enter any of the four interventions if they meet the appropriate entry criteria.
Intervention code [1] 318386 0
Treatment: Drugs
Comparator / control treatment
placebo controlled (normal saline IV infusion)
Control group
Placebo

Outcomes
Primary outcome [1] 324850 0
ARM 4:
time to clinical improvement (defined as a two point reduction in clinical progress ordinal scale) or discharge from hospital, whichever occurs first.
assessed using medical records
Timepoint [1] 324850 0
28 days from baseline
Secondary outcome [1] 385925 0
ARM 4: secondary outcome 1
Incidence of all cause death by day 28 and 60
Timepoint [1] 385925 0
day 28 from baseline and day 60 from baseline
Secondary outcome [2] 385926 0
ARM 4: secondary outcome 2
Time to all-cause mortality
Timepoint [2] 385926 0
any time up to 60 days from baseline
Secondary outcome [3] 385927 0
ARM 4: secondary outcome 3 - Composite outcome.
Illness severity of COVID-19, defined as the maximal score on the World Health Organization (WHO)’s clinical progression ordinal scale ranging from 0 (uninfected) to 10 (death)
a) Proportion who have recovered (defined as 0-4)
b) Proportion who had 1 point improvement
c) Proportion who had 2 point improvement
Timepoint [3] 385927 0
any time up to 60 days from baseline
Secondary outcome [4] 385928 0
ARM 4: secondary outcome 4
Incidence of ARDS.
assessed using medical records
Timepoint [4] 385928 0
any time up to 60 days from baseline
Secondary outcome [5] 385929 0
ARM 4: secondary outcome 5
incidence of HLH. assessed using medical records
Timepoint [5] 385929 0
any time up to 60 days from baseline
Secondary outcome [6] 385930 0
ARM 4: secondary outcome 6
Duration of hospitalisation. assessed using hospital medical records.
Timepoint [6] 385930 0
at discharge
Secondary outcome [7] 385931 0
ARM 4: secondary outcome 7
Proportion discharged from hospital. assessed using medical records
Timepoint [7] 385931 0
at discharge
Secondary outcome [8] 385932 0
ARM 4: secondary outcome 8
Incidence of mechanical ventilation up to day 28.
assessed using medical records
Timepoint [8] 385932 0
any time up day 28 from baseline
Secondary outcome [9] 385933 0
ARM 4: secondary outcome 9
composite outcome: Ventilator-free days and proportion who did not receive invasive mechanical ventilation. assessed using medical records
Timepoint [9] 385933 0
any time up to 60 days from baseline
Secondary outcome [10] 385934 0
ARM 4: secondary outcome 10
composite outcome: Organ failure free days and proportion who did not develop organ failure. assessed using medical records.
Timepoint [10] 385934 0
any time up to 60 days from baseline
Secondary outcome [11] 385935 0
ARM 4: secondary outcome 11
composite outcome: Incidence and duration of ICU admission. assessed using medical records
Timepoint [11] 385935 0
at discharge or by day 60 from baseline.
Secondary outcome [12] 385936 0
ARM 4: secondary outcome 12
composite outcome: incidence and duration of supplemental oxygen use. assessed using medical records
Timepoint [12] 385936 0
any time up to 60 days from baseline
Secondary outcome [13] 385937 0
ARM 4: secondary outcome 13
Time to clinical improvement defined as National Early Warning Score 2 (NEWS2) of <2 maintained for 24 hours.
assessed using medical records.
Timepoint [13] 385937 0
any time up to 60 days from baseline
Secondary outcome [14] 385938 0
ARM 4: secondary outcome 14
incidence of non-invasive ventilation. assessed using medical records
Timepoint [14] 385938 0
any time up to 60 days from baseline
Secondary outcome [15] 385939 0
ARM 4: secondary outcome 15
composite outcome: number of participants alive and off oxygen at day 60. assessed using medical records.
Timepoint [15] 385939 0
any time up to 60 days from baseline
Secondary outcome [16] 385940 0
ARM 4: secondary outcome 16
proportion of participants who had improved oxygenation for >48 hours. assessed using medical records
Timepoint [16] 385940 0
any time up to 28 days from baseline
Secondary outcome [17] 385941 0
ARM 4: secondary outcome 17
Incidence of adverse events based on the national cancer institute CTCAE v5
examples of possible/probable adverse events may include (but are not limited to):
• Infection of urinary tract
• Pain in limbs
• Headache
• Painful menstruation, typically involving abdominal cramps
• Throat pain
• Hot flush
Assessed using medical records and patient symptom diary.
Timepoint [17] 385941 0
any time up to day 28 from baseline.
Secondary outcome [18] 385942 0
ARM 4: secondary outcome 18
incidence of SAEs based on NCI CTCAE v5.
examples of possible/probable adverse events listed in known possible serious adverse events could include (but are not limited to):
• Heart attack
• Inflammation of the appendix (i.e. a pouch at the start of the large intestine)
• Infection of lungs
• Suicidal attempt
• Hypoxia - lack of sufficient oxygen in the tissues

This will be assessed using medical records
Timepoint [18] 385942 0
any time up to 28 days from baseline.
Secondary outcome [19] 385943 0
ARM 4: secondary outcome 19
change in nasopharngeal SARS-CoV-2 viral load shedding. assessed using qPCR.
Timepoint [19] 385943 0
any time up to day 60 from baseline

Eligibility
Key inclusion criteria
ARM 4
1. Age equal to or greater than 18 years of age.
2. Any haematological or solid tumour
3. Current or within the last 12 months received cancer related treatment such as chemotherapy, radiotherapy or targeted small molecule, cellular therapy or immune-modulating therapy
4. Signed written and verbal informed consent by participant or proxy capable of giving consent
5. Laboratory virological confirmation of SARS-CoV-2 by PCR as per local laboratory assays and COVID-19 diagnosis prior to randomisation
6. Hospitalised but has not required mechanical ventilation
7. Pneumonia diagnosed by chest x-ray or computed tomography (CT) revealing infiltrates consistent with pneumonia and SpO2 equal to or less than 94% on room air or requires low-flow oxygen supplementation or requires high-flow oxygen supplementation or non-invasive positive pressure ventilation (NIPPV).
8. Has not participated in other clinical trials for COVID-19 using an immunomodulating monoclonal antibody or kinase inhibitor. Note that participants on dexamethasone, corticosteroids, remdesivir, convalescent plasma and/or hydroxychloroquine with or without azithromycin are not excluded from the study. Agents that have received emergency use authorization and/or are considered by the study site to be standard treatment at the institution for COVID-19 are permitted provided the agent is not an immunomodulating monoclonal antibody or kinase inhibitor. Participation in clinical trials with remdesivir or convalescent plasma is permitted provided that all other eligibility criteria are met.
9. Females of childbearing potential must have a negative serum or urine pregnancy test at screening/baseline. Women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for 5 months following their last dose of study drug.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
ARM 4
1. Invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)
2. History of pulmonary alveolar proteinosis (PAP).
3. Women of childbearing potential who are pregnant or breastfeeding.
4. Known hypersensitivity to lenzilumab or any of its components.
5 .Use of any FDA-approved anti-IL-6 therapy (eg. tocilizumab, sarilumab, siltukimab), anti-IL-1 therapy (eg. anakinra, canakinumab) or kinase inhibitor (eg.baracitinib, ibrutinib, acalabrutinib) therapy to treat COVID-19 within 8 weeks prior to randomization. Any live vaccine within 8 weeks prior to randomisation. Note that subjects receiving other FDA-approved immunomodulators to treat underlying autoimmune disorders such as rheumatoid arthritis, psoriasis, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, atopic dermatitis, multiple sclerosis, etc. would not be excluded. Participants on corticosteroids or dexamethasone are not excluded from the study. Note: Participants on convalescent plasma, remdesivir and/or hydroxychloroquine with or without azithromycin are not excluded from the study.
6. Use of GM-CSF agents (e.g., sargramostim) within 8 weeks prior to randomisation.
7. Expected survival < 24h in the opinion of the investigator.
8. Any condition that, in the opinion of the investigator, is likely to interfere with the safety and efficacy of the study treatment or puts the subject at unacceptably high risk from the study.
9. Participation in another interventional study of COVID-19

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)
central randomisation
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
simple randomisation using computer software with stratification based on age (above and below 65 years old)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
sequential multiple assignment randomisation trial
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
By employing an Bayesian approach for directly inferring the probabilities of efficacy for each of the interventions proposed, the trial sample size is not required to be fixed in advance, which is of benefit given there is limited information required to derive expected sample size. However, we have provided an indicative sample size that would be required to identify a treatment effect for each primary hypothesis if using a more conventional, non-Bayesian approach. The expected sample sizes for each treatment arm (1:1 randomisation) are provided in the summary table and were calculated for 90% power and a 5% two-sided level of significance

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)
NSW,VIC
Recruitment hospital [1] 17296 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 17297 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [3] 17298 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [4] 17299 0
Westmead Hospital - Westmead
Recruitment hospital [5] 17300 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment postcode(s) [1] 31019 0
2145 - Westmead
Recruitment postcode(s) [2] 31016 0
3000 - Melbourne
Recruitment postcode(s) [3] 31017 0
3050 - Parkville
Recruitment postcode(s) [4] 31020 0
3065 - Fitzroy
Recruitment postcode(s) [5] 31018 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 306508 0
Government body
Name [1] 306508 0
Australian Government. Medical Research Future Fund
Address [1] 306508 0
Australian Government Department of Health Victorian Office
Level 8/595 Collins St, Melbourne VIC 3000
Country [1] 306508 0
Australia
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Centre
Address
305 Grattan Street.
Melbourne, Victoria
3000
Country
Australia
Secondary sponsor category [1] 307035 0
None
Name [1] 307035 0
Address [1] 307035 0
Country [1] 307035 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306710 0
Peter MacCallum HREC
Ethics committee address [1] 306710 0
305 Grattan Street.
Melbourne, Victoria
3000
Ethics committee country [1] 306710 0
Australia
Date submitted for ethics approval [1] 306710 0
13/07/2020
Approval date [1] 306710 0
21/08/2020
Ethics approval number [1] 306710 0

Summary
Brief summary
A multi-centre Australian trial with four arms aims to evaluate several different immune modulating drugs for prevention and treatment of COVID-19 specifically in the cancer population. This study arm (arm 4) is evaluating the effect of Lenzilumab on the treatment of COVID-19 infection in cancer patients with severe COVID-19 infection.

Who is it for?
You may be eligible to join this study arm if you are aged 18 and above, have any haematological or solid tumour, currently receiving cancer-related treatment, and are hospitalised with a severe COVID-19 infection

Study details
Participants in this study arm are randomly allocated (by chance) to one of two groups. One group will receive intravenous Lenzilumab over 24 hours while the other group will receive placebo intravenously over 24 hours.

Participants will be followed for 60 days to assess effectiveness and safety.

This study is one arm of a four arm, sequential multiple assignment randomisation trial where participants may become eligible and transition to different arms and treatments if they become exposed to COVID-19 or are hospitalised with an active moderate/severe COVID-19 infection.

It is hoped this research will provide insight into the best practice for prevention and treatment of COVID-19 in cancer patients as emerging standard of care measures are not always suitable to this especially vulnerable population.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 104754 0
Prof Monica Slavin
Address 104754 0
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne
Victoria
3000
Country 104754 0
Australia
Phone 104754 0
+61 3 8559 7997
Fax 104754 0
Email 104754 0
monica.slavin@petermac.org
Contact person for public queries
Name 104755 0
Mr Ronan Burder
Address 104755 0
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne
Victoria
3000
Country 104755 0
Australia
Phone 104755 0
+61 3 8559 5000
Fax 104755 0
Email 104755 0
ronan.burder@petermac.org
Contact person for scientific queries
Name 104756 0
Dr Michelle Yong
Address 104756 0
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne
Victoria
3000
Country 104756 0
Australia
Phone 104756 0
+61 3 8559 5000
Fax 104756 0
Email 104756 0
michelle.yong@petermac.org

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