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Trial registered on ANZCTR


Registration number
ACTRN12614000963628
Ethics application status
Approved
Date submitted
1/09/2014
Date registered
9/09/2014
Date last updated
10/07/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Detailed assessment of risks and benefits of inferior vena cava filters on patients with complicated injuries
Scientific title
Major trauma patients with inferior vena cava filters versus no prophylaxis in preventing venous thromboembolism
Secondary ID [1] 285261 0
NIL
Universal Trial Number (UTN)
Trial acronym
The da Vinci Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple trauma 292906 0
Venous thromboembolism 292907 0
Condition category
Condition code
Surgery 293195 293195 0 0
Surgical techniques
Blood 293196 293196 0 0
Clotting disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The filter should be inserted within 72 hours of admission to the study center
Intervention code [1] 290157 0
Treatment: Devices
Intervention code [2] 290192 0
Prevention
Comparator / control treatment
No early venous thromboembolism prophylaxis
Control group
Active

Outcomes
Primary outcome [1] 293080 0
Symptomatic pulmonary embolism confirmed by CT pulmonary angiography
Timepoint [1] 293080 0
Day 90 post randomisation
Primary outcome [2] 293106 0
Death -all causes
Timepoint [2] 293106 0
Day 90 post randomisation
Secondary outcome [1] 310297 0
Lower limb deep vein thrombosis confirmed by lower limb ultrasonography
Timepoint [1] 310297 0
Day 90 post randomisation
Secondary outcome [2] 310341 0
Acute symptomatic pulmonary embolism within 7 days of randomisation confirmed by post-mortem examination or CT pulmonary angiography
Timepoint [2] 310341 0
Within 7 days of randomisation
Secondary outcome [3] 310342 0
Fatal pulmonary embolism
Timepoint [3] 310342 0
Day 90 post randomisation
Secondary outcome [4] 310343 0
Cost-effectiveness
Economic outcome analysis plan
This will comprise (a) the net resource cost of IVC compared to the status quo without IVC (cost analysis) and (b) comparison of net resource use with net health benefits (cost-effectiveness).

a) Cost analysis
The total cost of treatment using an IVC filter includes the device itself, the consumables required for insertion and removable, the costs of personnel required for the procedure and costs of complications. Cost components for both arms of the trial which require analysis include length of index hospital stay including number of days in ICU, readmission days including ICU, pharmaceuticals required to treat PE, DVT prophylaxis, associated investigations including all X-rays, CT pulmonary angiography, ultrasonography and any other associated procedures. Follow-up will extend to 90 days post procedure in the first instance; furthermore, long-term outcomes including survival and venous thromboembolic complications & the cost-effectiveness in preventing these complications beyond day-90 will be assessed through use of linked health data as a sub-study. Costs will be drawn from hospital finance data where possible, but all resources will be collected in standard units and otherwise quantified using standard Australian resource data such as the MBS for medical procedures and the PBS for pharmaceuticals. Costs will be standardized to 2015 Australian dollars. The cost analysis will take the perspective of the Australian Health system.

Current cost data estimates:
It is estimated that the total cost of the procedure using IVF filters is approximately $6,000, comprising: $3000 - IVF filter, $3000 - consumables for insertion + labour costs for insertion and removal. Given the significant number needed to treat (estimated to be 10), net savings are unlikely to accrue unless additional individual benefits are evident such as survival and venous insufficiency after VTE. Given estimates of 20% expected DVT and 9-10% expected PE in the study cohort, the device will only be cost saving if PE costs on average, more than A$60,000.
However, if there is a difference in life saved after the use of IVC filters – that is a reduction in fatal PE as suggested by existing observational studies – this will contribute enormously to cost-effectiveness (as distinct from cost savings).

b) Cost-effectiveness
Costs of the procedure will be compared to health outcomes as determined from the trial.
The cost analysis as described above will indicate whether IVC filters provide a net saving to the health care system. A net saving in costs combined with a net health benefit suggests a dominant health intervention strategy. In the event that the IVC filters demonstrate health benefits at some cost, formal cost-effectiveness analysis can provide information around the relative health benefits for a given cost, compared to alternative resource demands, such as comparable procedures.

Using mortality outcomes, both at 90 days after admission and long-term after hospital discharge obtained by linked health data, cost per LYG (life year gained) can be estimated. Long-term outcomes will be analysed as a sub-study through data-linkage. If funding for this sub-study is not available, long-term outcome will be estimated using Markov decision analysis based on probabilities from the literature. Sensitivity analysis will be undertaken to test robustness of the parameters, to identify cost drivers and to estimate conditions under which the procedure is cost-effective. Cost-effectiveness ratios can be compared with similar procedures to estimate potential acceptability for wider policy.
Timepoint [4] 310343 0
1-year post randomisation

Eligibility
Key inclusion criteria
Patients will be eligible for the trial (1) if they are considered to have contraindications to pharmacologic thromboprophylaxis within 72 hours of hospital admission by their attending trauma or neurosurgeons AND (2) Injury Severity Score >15.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Severe head or systemic injury where death within 48 to 72 hours is expected.
2. Attending clinicians judge that patients are at low-risk of bleeding and can receive pharmacologic thromboprophylaxis within 3 days after major trauma.
3. Patients who have CT evidence of pulmonary embolism on admission to the hospital after trauma.
4. Patients who have been treated with full systemic anticoagulation by warfarin, UFH or LMWH for a pre-existing medical disease (e.g. patients with chronic atrial fibrillation requiring systemic anticoagulation) until admission due to trauma.
5. Pregnant patients.

Specific contraindications to heparin or other form of pharmacologic thromboprophylaxis are listed below.
1. Intracerebral haematoma or contusions
2. Active bleeding on admission requiring more than 6 units of blood transfusion within the first 24 hours of admission after the injury
3. Spinal cord injury resulting in neurological deficits or spinal cord haematoma is demonstrated in the MRI scan of the spine
4. Complex pelvic fractures resulting in significant retroperitoneal haematoma
5. Complex visceral organ injuries (e.g. splenic and liver lacerations) resulting in high risk of intraperitoneal bleeding
6. Others, please specify

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Web-based randomisation and allocation of treatment involving contacting the holder of the allocation schedule who is “off-site” or at central administration site
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Web-based random number generator created by computer software (i.e. computerised sequence generation), stratified by study sites.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Although IVC filters are increasingly used for thromboprophylaxis in many trauma patients, their clinical effectiveness has never been well documented. They are invasive, expensive and have significant complications some of which are life-threatening. It is important to demonstrate clinical superiority before they are widely used in patients who are already at risk of mortality and, hence, a superiority trial rather than a non-inferiority trial is preferred. We are planning a study of independent intervention (IVC filters) and active controls with 1 control per intervention subject. The incidence of asymptomatic PE between 3 and 7 days after moderate to major trauma is extremely high (24%) despite LMWH or UFH prophylaxis. Prior data indicate that the PE rate among patients who are at high-risk of VTE without thromboprophylaxis (similar to our control patients) is >0.09 (or 9%). The relatively high incidence of PE is expected because (a) we use a proactive approach to detect mildly symptomatic PE, and (b) we have chosen the group of trauma patients who are at extreme risk of VTE and, at the same time, cannot receive pharmacologic thromboprophylaxis and lower limb compression. The TESS score of these patients is expected to be >10. Evidence suggested that IVC filters are highly effective in reducing PE. If the PE rate of the intervention group is close to 0.5%, we will need to study 97 intervention subjects and 97 active control subjects to be able to reject the null hypothesis that the failure rates for intervention and active control subjects are equal with probability (power) 0.8 (or 0.9 if the baseline risk of PE is 10%). We assume there will be a small proportion of patients who will have study intervention crossed over between the two groups. Therefore the total sample size of this study is 240 (120 per group) allowing up to 20% of the study subject crossed over between the active control and intervention groups without affecting the power of the study. If an IVC is associated with an increased risk of lower limb DVT, this sample size will also have >80% power to detect an increased risk of DVT due to the IVC filter from 10% to 25%.




Chi-square statistics for categorical outcomes.

Cox proportional hazard regression for time to primary outcome after adjusting for important baseline covariates

Recruitment
Recruitment status
Completed
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)
WA
Recruitment hospital [1] 2947 0
Royal Perth Hospital - Perth
Recruitment hospital [2] 2948 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [3] 6616 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [4] 6617 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 14223 0
4029 - Herston
Recruitment postcode(s) [2] 14224 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 289892 0
Government body
Name [1] 289892 0
State Health Research Advisory Council, Department of Health, Western Australia
Address [1] 289892 0
SHRAC, Level 2, C Block, Department of Health, 189 Royal Street, East Perth, Perth, WA 6004
Country [1] 289892 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Medical Research Foundation, Royal Perth Hospital
Address
MRF Building, Perth, Royal Perth Hospital, PO Box 2323, East Perth, WA 6892
Country
Australia
Secondary sponsor category [1] 288577 0
None
Name [1] 288577 0
Address [1] 288577 0
Country [1] 288577 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291615 0
Royal Perth Hospital
Ethics committee address [1] 291615 0
Wellington Street, Royal Perth Hospital, WA 6000
Ethics committee country [1] 291615 0
Australia
Date submitted for ethics approval [1] 291615 0
01/10/2014
Approval date [1] 291615 0
22/10/2014
Ethics approval number [1] 291615 0
EC14-139
Ethics committee name [2] 291616 0
WA Coroner's Ethics Committee
Ethics committee address [2] 291616 0
WA Coroner's Office, 10th floor, Central Law Courts
501 Hay Strret, Perth, WA 6000
Ethics committee country [2] 291616 0
Australia
Date submitted for ethics approval [2] 291616 0
15/08/2014
Approval date [2] 291616 0
20/08/2014
Ethics approval number [2] 291616 0
EC03-14
Ethics committee name [3] 293607 0
Sir Charles Giardner Hospital Ethics Committee
Ethics committee address [3] 293607 0
Level 2 A Block, Hospital Avenue, Nedlands, WA 6009
Ethics committee country [3] 293607 0
Australia
Date submitted for ethics approval [3] 293607 0
Approval date [3] 293607 0
17/04/2015
Ethics approval number [3] 293607 0
2014-161

Summary
Brief summary
Venous thromboembolism (VTE) is a significant health problem especially in hospitalized patients, with a high associated morbidity and mortality. For most patients, the standard of care is to use prophylactic anticoagulation (heparin) and intermittent pneumatic compression to both lower limbs. There is a group of patients who are at very high risk of VTE but these VTE prophylactic measures cannot be used or considered adequate, either for physical reasons (lower limb fractures / open wounds ) or risk of bleeding from anticoagulants (such as severe brain injury). In these patients, the options are to use no intervention or to insert an Inferior Vena Cava filter (IVCF). Although IVCFs are widely used as a mechanical VTE prophylaxis in patients who have contraindications to conventional VTE prophylactic measures, their effectiveness in this regard has not been established. This phase II / III randomized controlled trial aims to assess the clinical effectiveness, benefits and harms, and also the cost- effectiveness of the early use of IVCFs (<72 hrs of admission after severe injury) for trauma patients who have contraindications to conventional VTE prophylactic measures (pharmacological thromboprophylaxis). This trial has the capacity to influence the management of trauma patients worldwide, and to establish the place of IVCFs in modern medical practice.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 51114 0
A/Prof Kwok Ming Ho
Address 51114 0
ICU, 4th Floor, North Block, Royal Perth Hospital, Wellington Street, Perth, WA 6000
Country 51114 0
Australia
Phone 51114 0
61-08-92241056
Fax 51114 0
61-08-92243668
Email 51114 0
kwok.ho@health.wa.gov.au
Contact person for public queries
Name 51115 0
A/Prof Kwok Ming Ho
Address 51115 0
ICU, 4th Floor, North Block, Royal Perth Hospital, Wellington Street, Perth, WA 6000
Country 51115 0
Australia
Phone 51115 0
61-08-92241056
Fax 51115 0
61-08-92243668
Email 51115 0
kwok.ho@health.wa.gov.au
Contact person for scientific queries
Name 51116 0
A/Prof Kwok Ming Ho
Address 51116 0
ICU, 4th Floor, North Block, Royal Perth Hospital, Wellington Street, Perth, WA 6000
Country 51116 0
Australia
Phone 51116 0
61-08-92241056
Fax 51116 0
61-08-92243668
Email 51116 0
kwok.ho@health.wa.gov.au

No data has been provided for results reporting
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary