Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619001193167p
Ethics application status
Not yet submitted
Date submitted
26/06/2019
Date registered
27/08/2019
Date last updated
27/08/2019
Date data sharing statement initially provided
27/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Anticoagulant (Apixaban Vs Warfarin) in prevention of nephrotic syndrome associated thromboembolism
Scientific title
Prospective, Open-Label, Randomized Control Trial on Efficacy of Highly Protein Bound New Oral Anticoagulant (Apixaban Vs Warfarin) in Prevention of Primary Nephrotic Syndrome Associated Thromboembolic Disease.
Secondary ID [1] 298423 0
None
Universal Trial Number (UTN)
U1111-1234-7759
Trial acronym
No acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Primary nephrotic syndrome 313154 0
Condition category
Condition code
Renal and Urogenital 311623 311623 0 0
Kidney disease
Blood 311624 311624 0 0
Clotting disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Apixaban 2.5mg tablet will be given twice a day orally for 2-6 months or until serum albumin is improved >25g/L with specific therapy (ie. immunosuppressant) for nephrotic syndrome, whichever occurs first .

Type, dose and duration of immunosuppressants (steroid, calcineurin inhibitor, mycophenolate, rituximab) will depend on a cause of nephrotic syndrome as guided by a clinical guideline (https://kdigo.org/guidelines/gn/) and patients' tolerability of the drug. Type, dose and duration of immunosuppressants and changes of the treatment plan will be chosen by a primary specialist or in-charge clinician after receiving an informed consent from the patient.

Renal pharmacist will contact patient and chemist to make sure that patient is compliant with medications.
Intervention code [1] 314674 0
Treatment: Drugs
Comparator / control treatment
Warfarin will be given once a day (5mg on day 1 and 2, then subsequent dose will depend on INR result) orally for 2-6 months or until serum albumin is improved >25g/L with specific therapy (ie. immunosuppressant) for nephrotic syndrome, whichever occurs first . Target INR is between 2-3. INR level (blood test) will be checked as per standard clinical protocol.

Type, dose and duration of immunosuppressants (steroid, calcineurin inhibitor, mycophenolate, rituximab) will depend on a cause of nephrotic syndrome as guided by a clinical guideline (https://kdigo.org/guidelines/gn/) and patients' tolerability of the drug. Type, dose and duration of immunosuppressants and changes of the treatment plan will be chosen by a primary specialist or in-charge clinician after receiving an informed consent from the patient.

Renal pharmacist will contact patient and chemist to make sure that patient is compliant with medications.
Control group
Active

Outcomes
Primary outcome [1] 320319 0
Efficacy of anticoagulant (ie. free from deep vein thrombosis, pulmonary embolism, renal vein thrombosis) will determined clinically. If patients have symptoms of deep vein thrombosis (leg swelling or pain), pulmonary embolism (chest pain, shortness of breath, palpitation, reduced oxygen level) and renal vein thrombosis (back or flank pain, deterioration of kidney function), Doppler ultrasound , VQ scan and CT scan will be used to detect suspected clinical problems.
Timepoint [1] 320319 0
anticoagulant (apixaban and warfarin) will be ceased when nephrotic syndrome patient is treated with specific therapy (ie. immunosuppressant) and their serum level >25g/l. Patient will be assessed weekly in the first month and then monthly for 6 months.
Primary outcome [2] 320320 0
Safety anticoagulant (ie. major and minor bleeding) will be assessed weekly in the first month and then monthly for 6 months. A major bleeding is defined by need for blood transfusion or endoscopic procedure or surgery or intervention to control bleeding. Any type of bleeding not requiring blood transfusion or endoscopic procedure or surgery or intervention to control bleeding is defined as a minor bleeding.

Assessment of major and minor bleeding will be done based on history, physical examination and routine blood tests (full blood count examination and coagulation profile) during routine clinic visits, telephone follow-up and whenever clinically indicated,
Timepoint [2] 320320 0
Anticoagulant (warfarin or apixaban) will be ceased when nephrotic syndrome patient is treated with specific therapy and their serum level >25g/l or when a major bleeding develops.
When major bleeding happens, patient will be assessed and managed daily until clinically safe. Appointment for subsequent reviews will be scheduled accordingly as per instructions of clinician in charge.
Secondary outcome [1] 371234 0
Adequacy of anticoagulants is assessed by blood tests.
Control (warfarin): INR blood tests as per a routine protocol
Intervention (apixaban): plasma anti-Xa activity and serum apixaban level
Timepoint [1] 371234 0
Adequacy of anticoagulants is confirmed with blood tests of INR for patients receiving warfarin and plasma anti-Xa activity and serum apixaban level for those taking apixaban.

If INR < 2,0, anticoagulation is inadequate, >3.0 is over therapeutic and the dose adjustment will be performed as per instructions of clinician in charge.

Although, routine therapeutic monitoring of anti-Xa activity and apixaban level is not routinely done because of the drug's relatively wide therapeutic index, measurement of levels will inform clinicians regarding patient compliance and adherence to therapy as well as in situations of suspected or known under or overdose. A 2.5 mg twice/day dose should yield a median apixaban maximum concentration of 77 ng/mL with a 41-146 ng/mL range for the 5th to 95th percentile, a median apixaban minimum concentration of 51 ng/mL (23,109), a median anti-Xa activity maximum value of 1.3 IU/mL (0.67, 2.4), a median anti-Xa activity minimum value of 1.2 IU/mL (0.51-2.4),as observed in patients whose had an elective hip or knee replacement and received 2.5mg twice/day for prevention of venous thromboembolism in the ARISTOTLE trial. Blood samples will be collected twice to measure apixaban levels 1 week after commencement of apixaban. The trough level (pre-dose) will represent minimum concentration of apixaban (C min) and the peak level at 3-4 hours after oral administration will be regarded as maximum concentration of apixaban (C max). Simultaneously, the anti-Xa activity in the plasma will be assessed. Blood sampling will be performed just before the dose (anti-Xa activity minimum) and 3-4 hours after oral administration (anti-Xa activity maximum).
Apixaban and anti-Xa levels will be checked in the first few weeks of enrolment as mentioned above and whenever clinically indicated. INR will be measured as per a routine clinical protocol and whenever clinically indicated. When a major bleeding happens, patient will be assessed and managed daily until clinically safe. Appointment for subsequent reviews will be scheduled accordingly as per instructions of clinician in charge.

Eligibility
Key inclusion criteria
Adult Primary Nephrotic Syndrome patients with Albumin <25gL
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
eGFR <30
Chronic Liver Disease
Bleeding disorders
Hb<10g/L
Acute bleeding in 3 months
Inducers and inhibitors CYP3A44 and P-gp

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



Intervention assignment
Parallel
Other design features
Phase
Phase 3 / Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
3/02/2020
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
270
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD

Funding & Sponsors
Funding source category [1] 302975 0
Hospital
Name [1] 302975 0
Royal Brisbane Women Hospital
Country [1] 302975 0
Australia
Primary sponsor type
Hospital
Name
Royal Brisbane Women Hospital
Address
Butterfield St, Herston QLD 4029
Country
Australia
Secondary sponsor category [1] 303683 0
None
Name [1] 303683 0
Address [1] 303683 0
Country [1] 303683 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 303527 0
Royal Brisbane and Women’s Hospital Human Research Ethics Committee
Ethics committee address [1] 303527 0
Ethics committee country [1] 303527 0
Australia
Date submitted for ethics approval [1] 303527 0
29/11/2019
Approval date [1] 303527 0
Ethics approval number [1] 303527 0

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

Contacts
Principal investigator
Name 93970 0
Dr Zaw Thet
Address 93970 0
Central QLD Hospital & Health Service
Renal Unit
Canning Street, Rockhampton
QLD 4700
Country 93970 0
Australia
Phone 93970 0
+61 749325319
Fax 93970 0
Email 93970 0
zaw.thet@health.qld.gov.au
Contact person for public queries
Name 93971 0
Zaw Thet
Address 93971 0
Central QLD Hospital & Health Service
Renal Unit
Canning Street, Rockhampton
QLD 4700
Country 93971 0
Australia
Phone 93971 0
+61 749325319
Fax 93971 0
Email 93971 0
zaw.thet@health.qld.gov.au
Contact person for scientific queries
Name 93972 0
Zaw Thet
Address 93972 0
Central QLD Hospital & Health Service
Renal Unit
Canning Street, Rockhampton
QLD 4700
Country 93972 0
Australia
Phone 93972 0
+61 749325319
Fax 93972 0
Email 93972 0
zaw.thet@health.qld.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Needs to discuss among investigators


What supporting documents are/will be available?

Current supporting documents:

Updated to:
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.