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Trial registered on ANZCTR


Registration number
ACTRN12620001128987
Ethics application status
Approved
Date submitted
2/09/2020
Date registered
30/10/2020
Date last updated
19/11/2021
Date data sharing statement initially provided
30/10/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of enoxaparin (a low molecular weight heparin) given in a single or split dose, on stroke occurrence after unruptured brain aneurysm treatment utilising coils or stents
Scientific title
Effect of single versus split dose enoxaparin post elective neurointervention on occurrence of thromboembolic events – a randomised study
Secondary ID [1] 302189 0
Nil known
Universal Trial Number (UTN)
U1111-1257-6541
Trial acronym
EPPICS II
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Intracranial Aneurysm 318862 0
Intracranial Lesions 318863 0
Condition category
Condition code
Stroke 316865 316865 0 0
Ischaemic
Cardiovascular 316866 316866 0 0
Diseases of the vasculature and circulation including the lymphatic system
Neurological 316867 316867 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants who have elective endovascular treatment of unruptured intracranial aneurysms requiring anticoagulation post procedure will be randomised to receive subcutaneous injections of either
1) enoxaparin 1mg/kg at T=0 and T=12hrs (split dose); or
2) enoxaparin 1.5mg/kg at T=0 (single dose)
(T=0 refers to end of procedure)

Enoxaparin administration will be confirmed by reviewing the medication chart, nursing and/or medical progress notes. The operating interventional neuroradiologist does not know the trial arm allocation till the procedure is concluded.
Intervention code [1] 318493 0
Treatment: Drugs
Comparator / control treatment
Enoxaparin 1.5mg/kg at T=0 (single dose)

The outcomes of the above group will be compared with the group given enoxaparin 1mg/kg at T=0 and T=12hrs (split dose)
Control group
Active

Outcomes
Primary outcome [1] 324977 0
The proportion of patients per group who develop thromboembolic events detected as lesions on diffusion weight imaging(DWI) MRI.
Timepoint [1] 324977 0
Post-procedural MRI will be performed within 48 hours after endovascular treatment of intracranial aneurysms

Primary outcome [2] 325288 0
Thromboembolic events will be further characterised as clinically evident(i.e. with signs of neurological deficit on examination) or clinically silent (radiological evidence without overt neurological deficit)

Neurological examination includes level of consciousness (Glasgow Coma Scale), cranial nerve, upper and lower limb examination
Timepoint [2] 325288 0
Neurological Examination will be performed within 24 hours of conclusion of the endovascular procedure
Secondary outcome [1] 386407 0
The proportion of patients who experience a puncture site complication (e.g.haematoma, application of a compression device or surgical intervention)
Timepoint [1] 386407 0
Puncture site observations are routinely carried out 3-6hourly for 24-48hours post procedure while an inpatient
Secondary outcome [2] 386408 0
The frequency of haemorrhage (major and minor) compared between anticoagulation arms.

a. Major haemorrhage – A clinically overt haemorrhage resulting in a fall of more than 30 g/L in haemoglobin; or a retroperitoneal, intracranial or intraocular haemorrhage. This is assessed through review of medical records, blood tests and MRI

b. Episodes of bleeding that were clinically overt but do not meet these criteria are considered minor haemorrhages. This is assessed through review of medical records and blood tests
Timepoint [2] 386408 0
Within 48 hours post-endovascular treatment of intracranial aneurysm

Eligibility
Key inclusion criteria
Patients admitted for elective endovascular treatment of intracranial aneurysm are eligible for inclusion.

Participants should understand the project and provide voluntary consent

Eligible patients will be admitted to the study if at the end of the endovascular procedure the operator determines that a period of post procedural anticoagulation is clinically indicated. The three most common reasons for this are:

1) Placement of an indwelling endovascular device, such as a stent
2) Presence of procedural platelet aggregation
3) Perceived increased risk of thromboembolic events due to
(3a) large area of coil exposure at aneurysm neck
(3b) loop protrusion into parent artery
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Under 18 years of age (i.e. paediatric population)
- Patients presenting with acute subarachnoid haemorrhage
- Patients with significantly impaired renal function (eGFR < 30)
- Patients not suitable for 3T MR imaging (e.g. pacemakers)
- Pregnant women
- Patients deemed not to require anti-coagulation post-procedure

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)
At the conclusion of the procedure, the operating interventional neuroradiologist will be given a sealed opaque envelope containing the allocation group
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerised sequence generation - simple randomisation using a randomisation table created by computer software
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/efficacy
Statistical methods / analysis
Number of participants:
Sample size calculations were performed using a two-sided pooled Z test based on 80% power and equal number allocation to each group. With a clinically meaningful absolute decrease of 0.25, a type I error rate (a) of 0.05 and an estimated 0.64 of patients developing a new DWI lesion post-procedure, 62 participants are required for each of the two arms. Therefore we aim to recruit a total of 124 participants.

Statistical analysis:
This will be done in conjunction with the QIMR Berghofer Statistics Unit.
The primary endpoint will be the proportion of patients with new DWI lesions detected on post procedure MRI for each arm. We will further determine whether there are differences between the arms with respect to the secondary endpoints of the proportion of patients who experience puncture site or haemorrhagic complications. Characteristics of each arm will be summarised using frequency and percent, mean and standard deviation for normally distributed continuous variables and median and interquartile range for non-normally distributed continuous variables. Chi-square tests will be used to compare randomised groups for categorical outcomes (includes primary outcome), t-tests for continuous normally distributed outcomes and Mann-Whitney U tests for continuous non-normally distributed outcomes.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
9/11/2020
Actual
10/02/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
124
Accrual to date
35
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 17382 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 31111 0
4029 - Herston

Funding & Sponsors
Funding source category [1] 306615 0
Hospital
Name [1] 306615 0
Royal Brisbane and Women's Hospital
Country [1] 306615 0
Australia
Funding source category [2] 307099 0
Other
Name [2] 307099 0
The Royal Australian and New Zealand College of Radiologists (RANZCR)
Country [2] 307099 0
Australia
Primary sponsor type
Individual
Name
Professor Alan Coulthard
Address
Department of Medical Imaging
Royal Brisbane and Women's Hospital
L3 Ned Hanlon Building
Butterfield Street
Herston, QLD 4029
Country
Australia
Secondary sponsor category [1] 307144 0
Hospital
Name [1] 307144 0
Royal Brisbane and Women's Hospital
Address [1] 307144 0
Butterfield Street
Herston, QLD 4029
Country [1] 307144 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306796 0
Royal Brisbane and Women’s Hospital HREC
Ethics committee address [1] 306796 0
Royal Brisbane and Women’s Hospital
Butterfield St
Herston QLD 4029
Ethics committee country [1] 306796 0
Australia
Date submitted for ethics approval [1] 306796 0
31/08/2020
Approval date [1] 306796 0
15/10/2020
Ethics approval number [1] 306796 0
HREC/2020/QRBW/67967

Summary
Brief summary
Thromboembolic events are frequent adverse events in neurointerventional procedures such as cerebral aneurysm coiling and stenting. Ischaemic lesions are visible on MRI diffusion weighted imaging (DWI). These can be further characterised as clinically evident or clinically silent. They are clinically evident ischaemic lesions(CEIL) if a neurological deficit is present, or clinically silent ischaemic lesions (CSIL) if not.

Most ischaemic strokes occur 4-12 hours post procedure. The overall incidence of DWI lesions post endovascular cerebral aneurysm treatment has been reported as 49-60% and the literature suggests that they can increase the risk of dementia and cognitive decline.

To assess the efficacy of enoxaparin (a low molecular weight heparin) in prevention of thromboembolic events, patients will be randomised to receive one of two enoxaparin dose regimens post elective endovascular aneurysm treatment:
(A) subcutaneous enoxaparin 1mg/kg at T=0 and T=12hrs (split dose); or
(B) subcutaneous enoxaparin 1.5mg/kg (single dose) at T=0.
T=0 refers to the end of the endovascular procedure.
Each patient will have pre and post-procedure MRIs.

The primary outcome of interest is the proportion of patients who have thromboembolic events assessed by neurological examination at 24 hours and MRI at 48hrs. Secondary outcomes include the frequency of puncture site complications and haemorrhage assessed through clinical monitoring.

We hope to learn which enoxaparin dose regimen should be recommended to neurointerventionists.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 105054 0
Prof Alan Coulthard
Address 105054 0
Department of Medical Imaging
L3 Ned Hanlon Building
Royal Brisbane and Women's Hospital
Butterfield Street
Herston, QLD 4029
Country 105054 0
Australia
Phone 105054 0
+61 7 3646 8111
Fax 105054 0
Email 105054 0
[email protected]
Contact person for public queries
Name 105055 0
Marita Prior
Address 105055 0
Department of Medical Imaging
Royal Brisbane and Women's Hospital
Butterfield Street
Herston, QLD 4029
Country 105055 0
Australia
Phone 105055 0
+61 7 3646 8111
Fax 105055 0
Email 105055 0
[email protected]
Contact person for scientific queries
Name 105056 0
Rebecca Liong
Address 105056 0
Department of Medical Imaging
Royal Brisbane and Women's Hospital
Butterfield Street
Herston, QLD 4029
Country 105056 0
Australia
Phone 105056 0
+61 7 3646 8111
Fax 105056 0
Email 105056 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.