Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000956808
Ethics application status
Approved
Date submitted
27/04/2021
Date registered
21/07/2021
Date last updated
14/03/2023
Date data sharing statement initially provided
21/07/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Comparing two anticoagulant treatment, Warfarin (Standard treatment) and Apixaban (A new treatment) in patients with a Mechanical Heart for bleeding and thrombosis complications.
Scientific title
Comparing Standard of Care Versus Apixaban in patients with a Ventricular Assist Device: a Parallel, randomised, non-inferiority, open label, control, pilot-study
Secondary ID [1] 302582 0
Nil known
Universal Trial Number (UTN)
U1111-1259-9356
Trial acronym
ApixiVAD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ventricular Assist Device (VAD) 319458 0
Bleeding 319461 0
Thrombosis 322066 0
Condition category
Condition code
Cardiovascular 317427 317427 0 0
Other cardiovascular diseases
Blood 317428 317428 0 0
Clotting disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention is the administration of apixaban, an oral tablet dosed at 2.5mg twice a day, in combination with an antiplatelet agent such as aspirin 100mg daily.

Patient receiving this intervention will remain on it until heart transplantation or until the end of the study (maximum of 24 months following randomisation).

Adherence to the intervention will be monitored with trough anti-Xa levels at baseline and then at a primary endpoint.

Intervention code [1] 318865 0
Treatment: Drugs
Comparator / control treatment
Standard of care anticoagulation with warfarin
- Dose is variable daily as dictated by serum international normalised ratio (INR) levels
- Duration of administration will be until transplantation or continued after the study period if the patient has not been transplantated
- Mode of administration is via oral tablets
- Adherence is monitored with INR levels
Control group
Active

Outcomes
Primary outcome [1] 325464 0
Composite endpoint comprised of the following outcomes:
1. Death - prospectively assessed
2. Suspected or confirmed pump thrombosis - detected by increase in power consumption by VAD, laboratory testing showing evidence of haemolysis, imaging evidence of systemic arterial perfusion deficit
3. Ischaemic or haemorrhagic stroke - detected with neuroimaging (head computed tomography[CT])
4. Other thrombo-embolic events, excluding stroke and pump thrombosis - detected with CT imaging evidence of infarction in major bodily organs
5. Major bleeding - any internal or external bleeding requiring hospitalisation or transfusion of 4 or more units of packed red blood cells in 24hours, this will be assessed by data-linkage to medical records
Timepoint [1] 325464 0
All composite primary outcome components will be assessed from randomisation until
1. The first time that any of the components of the primary composite endpoint occur in participants
2. The participant undergoes heart transplantation
Secondary outcome [1] 388046 0
Incidence of death assessed prospectively on participant follow-up
Timepoint [1] 388046 0
Assessed at any time from enrolment until time of heart transplantation
Secondary outcome [2] 396075 0
Suspected pump thrombosis - detected by increase in power consumption by VAD, laboratory testing showing evidence of haemolysis, imaging evidence of systemic arterial perfusion deficit
Timepoint [2] 396075 0
Assessed at any time from enrolment until time of heart transplantation
Secondary outcome [3] 396076 0
Ischaemic or haemorrhagic stroke - detected with neuroimaging (head computed tomography[CT])
Timepoint [3] 396076 0
Assessed at any time from enrolment until time of heart transplantation
Secondary outcome [4] 396077 0
Other thrombo-embolic events, excluding stroke and pump thrombosis - detected with CT imaging evidence of infarction in major bodily organs
Timepoint [4] 396077 0
Assessed at any time from enrolment until time of heart transplantation
Secondary outcome [5] 396078 0
Major bleeding - any internal or external bleeding requiring hospitalisation or transfusion of 4 or more units of packed red blood cells in 24hours, this will be assessed by data-linkage to medical records
Timepoint [5] 396078 0
Assessed at any time from enrolment until time of heart transplantation
Secondary outcome [6] 396079 0
Haemostasis testing to determine level of anticoagulation achieved with either warfarin or apixaban, assessed with thrombin - anti-thrombin (TAT) testing / INR / anti-FXa trough levels at events
Timepoint [6] 396079 0
Assessed at any time from enrolment until time of heart transplantation
Secondary outcome [7] 396080 0
Incidence of pump thrombosis - detected by increase in power consumption by VAD, laboratory testing showing evidence of haemolysis, imaging evidence of systemic arterial perfusion deficit
Timepoint [7] 396080 0
Assessed at any time from enrolment until time of heart transplantation
Secondary outcome [8] 396081 0
Binary outcomes of thrombolysis in the setting of pump thrombosis - assessed as being a success or failure
- Successful pump-thrombolysis: no pump exchange or re-thrombolysis in the 30 days following the event, this will be assessed by data-linkage to medical records
- Failure of pump thrombolysis: patient requires a second dose of thrombolysis, a pump exchange or does not survive therapy, this will be assessed by data-linkage to medical records
Timepoint [8] 396081 0
Assessed at any time from enrolment until time of heart transplantation
Secondary outcome [9] 396082 0
Major haemolysis - assessed with laboratory markers of elevation of the lactate dehydrogenase (LDH) to the 2.5 time the upper limit of the norm (ULN) and/or elevation of the free Haemoglobin to > 40mg/dL
AND symptoms OR finding compatible with haemolysis with Symptomatic hemoglobinuria (“tea-coloured urine”)
Timepoint [9] 396082 0
Assessed at any time from enrolment until time of heart transplantation
Secondary outcome [10] 396083 0
Stroke characterisation assessed by adjudication of the type of stroke by consensus with a radiologist and a neurologist:
- Ischaemic stroke: acute infarction on imaging corresponding anatomically to the clinical deficit.
- Intracranial haemorrhage: new acute neurological deficit (this is will be assessed by physical clinical assessment of the patient) attributable to intracranial haemorrhage: Subarachnoid, Intraventricular, Parenchymal or subdural.
Timepoint [10] 396083 0
Assessed at any time from enrolment until time of heart transplantation
Secondary outcome [11] 396084 0
Stroke severity assessed with the Modified Rankin Score (mRS), which is a 6 point disability scale with possible scores ranging from 0 to 5. A separate category of 6 is added for patients who died. Standardized interviews to obtain a mRS score will be performed at 3 months (90 days) following hospital discharge after an ischaemic or haemorrhagic stroke
Timepoint [11] 396084 0
The incidence of strokes will be identified and assessed at any time from enrolment until time of heart transplantation.

A mRS will be assessed through standardised interviews at 3 months (90 days) following hospital discharge after an ischaemic or haemorrhagic stroke.
Secondary outcome [12] 396085 0
Non-major bleeding events assessed as any symptomatic bleeding not fulfilling the definition of major bleeding with the following questions asked of the participant

- Have you been hospitalised during the period between today and the last visit with the study team?
- Have you experienced black/tarry bowel motions since our last meeting? (stool with digested blood often has
an offensive smell and is sticky)
- Have you experienced red/bloody bowel motions?
- Have you vomited blood?
- Have you coughed up blood?
- Have you had any bleeding in your mouth?
- Have you had any bleeding from your nose?
- Have you had any bleeding or discolouration in your urine?
Timepoint [12] 396085 0
This will be assessed specifically at every formal follow-up timepoint, i.e. every three months until time of heart transplantation. It can also be assessed at any time from enrolment until time of heart transplantation if the patient reports any symptoms suggestive of non-major bleeding.
Secondary outcome [13] 396086 0
Baseline haemostasis will be assessed using Thrombin - anti-thrombin (TAT) measured at 1 and 3 months post randomization.
Timepoint [13] 396086 0
Assessed at 1 and 3 months after randomisation
Secondary outcome [14] 396087 0
Adherence to apixaban assessed using Anti-Xa trough levels measured (sample collected just before the next dose of apixaban). Because of the absence of therapeutic ranges, the result of this measurement will not be used to change the dose of apixaban.
Timepoint [14] 396087 0
Assessed at 1 and 3 months after randomisation
Secondary outcome [15] 396088 0
Time in therapeutic range (TTR) in the warfarin group assessed by audit of haematology results
Timepoint [15] 396088 0
Assessed at any time from enrolment until time of heart transplantation
Secondary outcome [16] 396089 0
Self-reported adherence to apixaban will be assessed by encouraging patients to complete the specifically designed questionnaire Apixaban "Follow up form”
Timepoint [16] 396089 0
Assessed every three months after randomisation until time of heart transplantation
Secondary outcome [17] 396090 0
Quality of life will be assessed using the assessment using the Anti-Clot Treatment Satisfaction score or ACTS79. This self-completed questionnaire (“Modified Anti-Clot Treatment Satisfaction form”) will be given to patients every three months to compare the satisfaction in both groups regarding their anticoagulation
Timepoint [17] 396090 0
Assessed every three months after randomisation until time of heart transplantation
Secondary outcome [18] 396091 0
Whether patients are taking digoxin, ACE-inhibitors, and PPIs will be recorded at each follow up visit in the patient's drug history
Timepoint [18] 396091 0
Assessed every three months after randomisation until time of heart transplantation
Secondary outcome [19] 396092 0
Infection will be detected by assessed for presence of symptoms compatible with a driveline infection and or of a systemic infection will be recorded at each visit
Timepoint [19] 396092 0
Assessed every three months after randomisation until time of heart transplantation.
Secondary outcome [20] 396093 0
30-day survival post transplantation will be assessed by monitoring the patient after transplantation
Timepoint [20] 396093 0
30 days after transplantation
Secondary outcome [21] 396094 0
The quantity blood products transfused if required during transplantation will be assessed by following the number of blood transfusion received by the patient during the transplantation and in the 30 days following transplantation. This outcome with be specifically assessed by data-linkage to medical records,
Timepoint [21] 396094 0
30 days after transplantation
Secondary outcome [22] 396095 0
The ICU length of stay following heart transplantation will be followed, assessed by data-linkage to medical records
Timepoint [22] 396095 0
At time of ICU discharge after heart transplantation

Eligibility
Key inclusion criteria
Patients implanted with a Left Ventricular Assist Device (LVAD) and fulfilling the following (inclusion) criteria:
- Patients implanted with a ventricular assist device in the left ventricle
- Patients actively following up in the mechanical circulatory support clinic at St. Vincent’s Hospital, Sydney
- Bodyweight greater than 60 Kg
- Patients aged between 18 and 70 years
- Creatinine clearance greater than 25ml/min and creatinine level < 221mcmol/l
- Participant able to give an informed consent
- TTR in the preceding 4 weeks of 60% or more
- Reason for VAD implantation is either as a bridge to decision (BTD) or a bridge to transplant (BTT)
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Stroke following VAD implantation (if occurred more than 4 weeks after VAD implantation)
- Major bleeding (if occurred more than 4 weeks after VAD implantation)
- Requirement for treatment with aspirin at a dose greater than 100 mg per day
- Simultaneous treatment with both aspirin and a thienopyridine (e.g., clopidogrel, prasugrel, ticagrelor)
- Women who are pregnant or breastfeeding
- Allergy to apixaban
- TTR <60% in the preceding 4 weeks
- Severe renal insufficiency (serum creatinine > 221mcmol/l or a calculated creatinine clearance < 25 mL/min)
- Alanine transaminase > 5x ULN or known cirrhotic liver disease
- Active alcohol or illicit drug use, or psychosocial reasons that make study participation impractical
- Patients with known Human Immunodeficiency Virus (HIV) infection
- Patients taking medications or other substances known to be potent inhibitors of the CYP3A4 enzyme (e.g. -azole antifungals (itraconazole and ketoconazole), macrolide antibiotics (clarithromycin and telithromycin), protease inhibitors (ritonavir, indinavir, nelfinavir, atazanavir, and saquinavir), and nefazadone)
- Patient taking medications or substances known to be potent inducers of the CAP3A4 enzyme (e.g. antituberculosis treatments (rifampicin))
- Allergy to any of component ingredients of Andexanet-alfa: tris, arginine, sucrose, hydrochloric acid, mannitol, and polysorbate 80 (if available).

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)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample Size Estimation: The pilot trial, Apixi-VAD will no reach statistical significance.

Given our estimated event rate of 35% for the primary outcome, based on current data, we expect that our sample size of 30 will be sufficient to demonstrate feasibility as well as an adverse safety signal. This pilot trial will not set out to determine statistical non-inferiority.

Analysis Plan:
- Descriptive statistical methods will be applied to depict the study population on risk factors, operative characteristics, and outcome.
- Continuous variables will be presented as mean and SD and compared with the independent samples t test between study groups.
- Total numbers and proportions will be reported for categorical outcomes and compared with the Fisher exact test.
- The Kaplan–Meier method with a log-rank test will be performed to compare event-free survival (no adverse event leading to study termination or death) and adverse events. The life table method with a Wilcoxon–Gehan test was used to calculate median time to study termination.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
13/10/2021
Actual
12/01/2022
Date of last participant enrolment
Anticipated
1/02/2024
Actual
Date of last data collection
Anticipated
18/11/2024
Actual
Sample size
Target
30
Accrual to date
21
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 19219 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 33792 0
2010 - Darlinghurst
Recruitment outside Australia
Country [1] 25323 0
Switzerland
State/province [1] 25323 0
Bern

Funding & Sponsors
Funding source category [1] 307013 0
Charities/Societies/Foundations
Name [1] 307013 0
Heart Failure Research Trust Fund
Country [1] 307013 0
Australia
Primary sponsor type
Hospital
Name
St.Vincent Hospital
Address
St.Vincent Hospital
390 Victoria Street
Darlinghurst NSW 2010
Country
Australia
Secondary sponsor category [1] 307583 0
Individual
Name [1] 307583 0
Christopher Hayward
Address [1] 307583 0
St.Vincent Hospital
390 Victoria Street
Darlinghurst NSW 2010
Country [1] 307583 0
Australia
Other collaborator category [1] 281515 0
Individual
Name [1] 281515 0
Bruno Schnegg
Address [1] 281515 0
Department of Cardiology (Universitätsklinik für Kardiologie, Inselspital Bern)
Freiburgstrasse 4
3010 Bern
Switzerland
Country [1] 281515 0
Switzerland

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307144 0
St Vincent's Hospital Sydney Human Research Ethics Committee (HREC)
Ethics committee address [1] 307144 0
Ethics committee country [1] 307144 0
Australia
Date submitted for ethics approval [1] 307144 0
02/04/2020
Approval date [1] 307144 0
31/05/2021
Ethics approval number [1] 307144 0
2020/ETH00695

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 106190 0
Prof Christopher Hayward
Address 106190 0
St.Vincent Hospital
390 Victoria Street
Darlinghurst NSW 2010
Country 106190 0
Australia
Phone 106190 0
+61 02 8382 6885
Fax 106190 0
+61 02 8382 6881
Email 106190 0
[email protected]
Contact person for public queries
Name 106191 0
Christopher Hayward
Address 106191 0
St.Vincent Hospital
390 Victoria Street
Darlinghurst NSW 2010
Country 106191 0
Australia
Phone 106191 0
+61 02 8382 6880
Fax 106191 0
+61 02 8382 6881
Email 106191 0
[email protected]
Contact person for scientific queries
Name 106192 0
Bruno Schnegg
Address 106192 0
Department of Cardiology (Universitätsklinik für Kardiologie, Inselspital Bern)
Freiburgstrasse 4
3010 Bern
Switzerland
Country 106192 0
Switzerland
Phone 106192 0
+41793957546
Fax 106192 0
Email 106192 0
[email protected]

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 Supporting Document Provided



Results publications and other study-related documents

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

Documents added automatically
No additional documents have been identified.