Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617000331336
Ethics application status
Approved
Date submitted
18/11/2016
Date registered
2/03/2017
Date last updated
5/02/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Anticoagulant therapy for cancer-associated blood clots
Scientific title
A Phase 2 study of safety of Rivaroxaban compared with Low Molecular Weight Heparin (LMWH) for acute therapy of cancer-associated venous thromboembolism
Secondary ID [1] 290547 0
Nil
Universal Trial Number (UTN)
U1111-1189-9501
Trial acronym
ACAT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer-associated thrombosis 300988 0
Venous Thromboembolism 302092 0
Deep Vein Thrombosis 302093 0
Pulmonary Embolism 302094 0
Condition category
Condition code
Blood 300784 300784 0 0
Clotting disorders
Cancer 300808 300808 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Study intervention will be commenced immediately after randomisation and within 72 hours (cohort R1) or between 30 +/- 2 days (cohort R2) after commencement of therapeutic anticoagulation according to initial consent and election for treatment.
Standard of care anticoagulant therapy is low molecular weight heparin of choice injected subcutaneously (protocol recommends dalteparin 200 IU /kg once daily as per Product Information) . The study intervention will be Rivaroxaban 15mg twice daily per oral for 3 weeks and then 20mg once daily thereafter.
Rivaroxaban: oral tablet
Duration of administration: 6 months
monitor adherence: clinic review
Cohort R1 refers to patients who are randomised to oral rivaroxaban or standard of care within 72 hours of diagnosis of venous thromboembolism.
Cohort R2 refers the patients who are randomised to oral tablet rivaroxaban or standard of care at timepoint 30 days +/- 2 days of diagnosis of venous thromboembolism..
Intervention code [1] 296419 0
Treatment: Drugs
Comparator / control treatment
The standard of care anticoagulation in this study is with LMWH. The best evaluated regimen is as published in the CLOT in Cancer with dalteparin (Fragmin) 200IU/kg given subcutaneously once daily (to a maximum dose of 18.000 IU per day) with a dose reduction to 150 IU/kg after 30 days. Enoxaparin either 1mg/kg twice daily with dose reduction to 1.5 mg/kg once daily after 30 days also acceptable. LMWH schedules will be adjusted for renal impairment.
Low molecular weight heparin is administered by subcutaneous injection as per usual standard of care.

The determination whether each participant will receive dalteparin or enoxaparin and the dose received will be at the discretion of the treating physician.
Control group
Active

Outcomes
Primary outcome [1] 300211 0
The primary endpoint of the study is the combined endpoint of clinically relevant non-major bleeding (CRNMB) and major (including fatal) bleeding. The definitions of these outcomes are stated in protocol and are diagnosed by the treating physician with corroboration from medical records. An independent outcome adjudication committee will verify all reported major bleeding events and a random selection (~10%) of CRNMB.
Timepoint [1] 300211 0
The primary endpoint will be evaluated at 6 months post randomisation.
Secondary outcome [1] 329409 0
Secondary endpoints include CRNMB major bleeding and fatal bleeding assessed individually and combined at 3 weeks.
Major bleeding and clinically relevant non-major bleeding will be assessed using the standard ISTH (International Society of Thrombosis and Haemostasis) bleeding assessment tool. Fatal bleeding is defined by death related to bleeding according to treating clinician.
Timepoint [1] 329409 0
3 weeks
Secondary outcome [2] 330133 0
Secondary endpoints include CRNMB major bleeding and fatal bleeding assessed individually and combined at 3 months,
Major bleeding and clinically relevant non-major bleeding will be assessed using the standard ISTH (International Society of Thrombosis and Haemostasis) bleeding assessment tool. Fatal bleeding is defined by death related to bleeding according to treating clinician.
Timepoint [2] 330133 0
3 Months post randomisation
Secondary outcome [3] 330135 0
Secondary endpoints include CRNMB major bleeding and fatal bleeding assessed individually and combined at 6 months (note this includes a combined endpoint of major and clinically relevant non-major bleeding at 3 weeks, 3 months and 6 months as a cumulative total) ,
Timepoint [3] 330135 0
6 month post randomisation
Secondary outcome [4] 330136 0
All cause mortality.
If patients do not attend planned 6 month followup, a phone call will be made to the family and a check of medical records will be instituted to determine if patient has died.
Treating physician will also be notified by palliative care units if patient dies in palliative care.
Timepoint [4] 330136 0
at 6 months post randomisation
Secondary outcome [5] 330137 0
Other vascular events (protocol states this includes myocardial infarction, stroke, other vascular thromboembolism).
Myocardial infarction will be defined by standard changes on ECG (electrocardiogram) associated with significant rise in blood troponin levels.
Stroke will be defined as sudden onset neurological deficit with or without evidence of changes on non-contrast CT brain scan or brain MRI scan.
Other vascular thromboembolism will be defined as clinical diagnosis of any other organ damage (non heart, non-brain) attributable to blood clot.
Timepoint [5] 330137 0
at 6 months post randomisation
Secondary outcome [6] 331283 0
Symptomatic and objectively confirmed recurrent vein thrombosis (either deep vein thrombosis at any site or pulmonary embolism).
Deep vein thrombosis will be confirmed using doppler ultrasound.
Pulmonary embolism will be confirmed using either ventilation/perfusion scan or CT pulmonary angiogram.
Timepoint [6] 331283 0
At 6 months after randomisation

Eligibility
Key inclusion criteria
1. Active malignancy defined by diagnosis of cancer (excluding non-melanomatous skin malignancy), recurrent cancer, or treatment for cancer within last 12 months.
2. Acute symptomatic and objectively proven VTE, either proximal DVT or PE, requiring therapeutic anticoagulation for at least 3 months.
3. Aged 18 years or older at time of inclusion
4. Patient eligible for PBS subsidised LMWH and rivaroxaban (supplied by authority prescriptions).
5. Able to attend outpatient clinic for follow-up assessment.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patient received >72 hours (Cohort R1) or >32 days (Cohort R2) weeks of therapeutic anticoagulation.
2. Cessation of therapeutic anticoagulation for > 24 hours once commenced.
3. Severe renal impairment defined by calculated GFR (Cockcroft-Gault) <30 mLs/minute. Significant hepatic disease (including moderate to severe hepatic impairment, i.e. Child-Pugh B and C) or ALT > 3 x ULN.
4. Concomitantly treated with strong inhibitors of both CYP 3A4 and P-glycoprotein such as HIV protease inhibitors (e.g. ritonavir) or systemically administered azole anti-mycotics (ketoconazole, itraconazole, posaconazole, voriconazole)
5. Clinically significant active bleeding such that full therapeutic anticoagulation is contraindicated
6. Serious haemorrhage within last 4 weeks requiring hospitalisation, transfusion or surgical intervention.
7. Investigator deem patient at high risk of bleeding on anticoagulation. Reasons may include (but not be restricted to) uncontrolled hypertension, recent surgery to brain spine or eye, recent gastro-duodenal ulceration, presence of coagulopathy (INR >1.5 or platelet count <60 x 10^9/l), significant familial bleeding tendency, absolute necessity for dual anti-platelet therapy.
8. Indication for long term anticoagulation (e.g. mechanical heart valve, prior stroke in context of AF)
9. Pregnant or of childbearing potential and not using adequate contraception
10. Expected life span <6 months and/or ECOG 4 at enrolment.
11. Geographically inaccessible for follow-up.

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 by phone/fax/computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be stratified according to randomisation cohort. clinical centre, type of VTE (DVT alone or PE), and planned duration of anticoagulant therapy.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
3/03/2017
Actual
4/04/2017
Date of last participant enrolment
Anticipated
31/12/2019
Actual
Date of last data collection
Anticipated
30/06/2020
Actual
Sample size
Target
600
Accrual to date
15
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
Recruitment hospital [1] 6944 0
Concord Repatriation Hospital - Concord
Recruitment hospital [2] 6945 0
Prince of Wales Hospital - Randwick
Recruitment hospital [3] 6946 0
Westmead Hospital - Westmead
Recruitment hospital [4] 6948 0
Box Hill Hospital - Box Hill
Recruitment hospital [5] 7497 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 14634 0
2031 - Randwick
Recruitment postcode(s) [2] 14633 0
2139 - Concord
Recruitment postcode(s) [3] 14635 0
2145 - Westmead
Recruitment postcode(s) [4] 14637 0
3128 - Box Hill
Recruitment postcode(s) [5] 15322 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 294991 0
Charities/Societies/Foundations
Name [1] 294991 0
Thrombosis and Haemostasis Society of Australia and New Zealand
Country [1] 294991 0
Australia
Primary sponsor type
Government body
Name
South East Sydney and Illawarra Area Health Service
Address
Barker St,
Randwick
NSW 2031
Country
Australia
Secondary sponsor category [1] 293810 0
Government body
Name [1] 293810 0
Sydney Local Health District
Address [1] 293810 0
Level 11,
KGV Building,
Missenden Road,
Camperdown
NSW 2050
Country [1] 293810 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296345 0
South Eastern Sydney Local Health Disctrict Human Research Ethics Committee
Ethics committee address [1] 296345 0
Room G71 East Wing
Edmund Blacket Building
Prince of Wales Hospital Randwick NSW 2031
Ethics committee country [1] 296345 0
Australia
Date submitted for ethics approval [1] 296345 0
28/11/2014
Approval date [1] 296345 0
20/01/2015
Ethics approval number [1] 296345 0
HREC/14/POWH/569

Summary
Brief summary
The primary purpose of this trial is to evaluate the safety of rivaroxaban for the treatment of thrombosis associated with cancer, in comparison to the standard care treatment with low molecular weight heparin (LMWH).

Who is it for?
You may be eligible to enroll in this trial if you are aged 18 or over and have active cancer and require therapeutic anticoagulation for a new diagnosis of deep vein thrombosis or pulmonary embolism. The duration of anticoagulant treatment should be for at least 6 months.

Study details
All participants enrolled in this trial will be randomly allocated (by chance) to receive either treatment with rivaroxaban or treatment as per standard care with LMWH for at least 6 months. Patients can either be enrolled within 72 hours of diagnosis, or at day 30 +/- 2 days. Participants will be assessed six months later for side effects of treatment, including any bleeding which has occurred.

It is hoped that the findings from this trial will provide information on whether rivaroxaban is a safe alternative to LMWH for the treatment of cancer-associated thrombosis.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 70494 0
Dr Timothy Brighton
Address 70494 0
SEALS, Level 4 Campus Centre Building
Prince of Wales Hospital, Barker St, Randwick
Sydney NSW Australia 2031
Country 70494 0
Australia
Phone 70494 0
+61293829013
Fax 70494 0
+61293829116
Email 70494 0
Timothy.Brighton@health.nsw.gov.au
Contact person for public queries
Name 70495 0
Vivien Chen
Address 70495 0
Haematology Concord Hospital
Hospital Rd
Concord NSW 2139
Country 70495 0
Australia
Phone 70495 0
+61297675763
Fax 70495 0
+61297677650
Email 70495 0
vivien.chen@sswahs.nsw.gov.au
Contact person for scientific queries
Name 70496 0
Timothy Brighton
Address 70496 0
SEALS, Level 4 Campus Centre Building
Prince of Wales Hospital, Barker St, Randwick
Sydney NSW Australia 2031
Country 70496 0
Australia
Phone 70496 0
+61293829013
Fax 70496 0
+61293829116
Email 70496 0
Timothy.Brighton@health.nsw.gov.au

No information has been provided regarding IPD availability


What supporting documents are/will be available?

Current supporting documents:


Updated to:
Doc. No.TypeCitationLinkEmailOther DetailsAttachment
23470Ethical approval   

Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
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