Clinical Trial Details
— Status: Completed
Administrative data
NCT number |
NCT03494530 |
Other study ID # |
Version 4.0 |
Secondary ID |
|
Status |
Completed |
Phase |
Phase 4
|
First received |
|
Last updated |
|
Start date |
June 1, 2018 |
Est. completion date |
December 1, 2021 |
Study information
Verified date |
April 2024 |
Source |
University of Alberta |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
Study Design:
Lixiana Acute Stroke Evaluation Registry (LASER) is a randomized controlled trial with an
associated registry. Patients with previously known or newly diagnosed atrial fibrillation
(AF) and acute ischemic stroke within five days will be randomized 2:1 to early (≤ 5 days) or
delayed (6-14 days) edoxaban initiation. Ischemic stroke will be defined as evidence of acute
focal cerebral infarction confirmed on CT/MRI and/or focal hypoperfusion/vessel occlusion on
multimodal CT, or by sudden focal and objective neurological deficits (i.e NIHSS ≥ 1) of
presumed ischemic origin persisting > 24 hours.
Study Aim and Objectives:
The primary aim of LASER is to demonstrate the safety of edoxaban initiation within five days
of cardioembolic stroke. Secondary aim is to determine predictors of hemorrhagic
transformation (HT) after cardioembolic stroke. Investigators will systematically assess
prospectively collected Computed Tomography (CT) scan images for evidence of HT and
re-infarction.
Description:
Study Hypothesis:
Investigators hypothesize that edoxaban initiation within five days of ischemic stroke will
not be associated with increased HT rates, relative to patients in whom anticoagulation is
delayed. Serial imaging using CT will be utilized to determine the rate of radiological HT
after edoxaban initiation. Incident radiological HT rates will be assessed as objective
performance criteria for the safety of early versus delayed edoxaban initiation.
Investigators also hypothesize that RNA expressed in leukocytes at time of stroke can
stratify risk of HT in patients treated with edoxaban. Investigators will assess the rate of
recurrent ischemic stroke, but recognize any differences between groups will be hypothesis
generating only due to the small trial sample size.
Study Design:
LASER is a randomized controlled, parallel-group, two-arm, assessor-blinded trial with an
associated registry. Patients with previously known or newly diagnosed AF-related ischemic
stroke within five days will be randomized 2:1 to early (≤ 5 days) or delayed (6-14 days)
edoxaban initiation. Ischemic stroke will be defined as evidence of acute focal cerebral
infarction confirmed on CT/MRI and/or focal hypoperfusion/vessel occlusion on multimodal CT,
or by sudden focal and objective neurological deficits (i.e NIHSS ≥ 1) of presumed ischemic
origin persisting > 24 hours. A total of one hundred fifty patients from a comprehensive
Canadian stroke center will be enrolled. Eligible patients will be randomized within five
days of symptom onset after baseline imaging. Patients with spontaneous parenchymal
hemorrhage (PH) (European Cooperative Acute Stroke Study (ECASS) grade PH1 or PH2 on the
baseline imaging will not be eligible for randomization. These patients will be included in
the registry portion of LASER and follow-up will be identical to that in the trial. The
timing of edoxaban initiation in these patients will be at the discretion of the treating
physician.
Eligible patients will be randomized 2:1 following open label simple randomization procedure
to early (≤ 5 days) or delayed (6-14 days) edoxaban initiation via a centralized web-based
randomization process, Research Electronic Data Capture (REDCap, Vanderbilt university).
After randomization to early or delayed arms, the decision to time the edoxaban initiation
within the specific arm will be at the treating physician's discretion. The rationale for the
specific timing of treatment, within the randomization window, will also be recorded by
surveying the treating physician in each case.
All randomized patients will be followed for 90 days after edoxaban initiation. A National
Institute of Health Stroke Scale (NIHSS) score will be assessed at baseline, 7 and 90 days
after edoxaban initiation. Functional outcome will be assessed with a modified Rankin Scale
(mRS) score at baseline, 7 and 90 days after edoxaban initiation. Montreal Cognitive
Assessment (MoCA) will be performed at baseline, and day 90 after edoxaban initiation. RNA
will be used to stratify risk of HT. Functional outcome at 90 days will be dichotomized as
favourable (mRS score 0-2) and unfavourable (mRS score 3-6). Quality of life will be assessed
with the EuroQol-5 Dimension (EQ-5D) and Visual Analog Scale (VAS) at day 90.
In addition to diagnostic imaging, all patients will have a non-contrast, axial CT scan at
baseline (within 24 hours from study recruitment) and at 7±2 days after edoxaban initiation.
Therefore, all patients will have a minimum of two scans (diagnostic and
pre-randomization).In the event of clinical deterioration, CT scans will be repeated. The
original LASER protocol included MRI acquisition in all patients. Following diagnostic CT,
all patients were to undergo MRI including diffusion-weighted imaging (DWI to assess the
acute infarct volume), Fluid Attenuated Inverse Recovery (FLAIR to assess chronic infarct and
white matter ischemic change volumes) and susceptibility weighted imaging (SWI to assess for
acute HT and chronic cerebral microbleeds) prior to randomization. Shortly after trial
initiation, however, COVID-19 restrictions limited access to research MRI protocols. The
protocol was therefore amended and both baseline and day 7 imaging data are limited to CT.
Administrative Structure:
Case report forms and data monitoring will be completed on site. All imaging data will be
read centrally at the Stroke Imaging Laboratory at the University of Alberta.
Procedures:
Randomized patients will be treated with edoxaban 60 mg once daily. The edoxaban dose will be
reduced to 30 mg once daily if any of the following characteristics are present at the time
of randomization or during the study: estimated creatinine clearance (CrCl) of 30 to 50 ml
per minute using Cockcroft-Gault Equation or body weight ≤ 60 kg. Prior to edoxaban
initiation, all patients will be treated as per the clinical standard of care using
antiplatelet(s) and anticoagulation for deep venous thrombosis (DVT) prophylaxis. Any
antithrombotic therapy prior to randomization will be recorded.
Imaging Procedures and Analysis:
Anonymized dicom CT data will be assessed by two independent raters, blinded to treatment
group, for the presence, number and total volume of regions with infarction. Infarct volumes
will be measured using planimetric techniques. Any HT, as well as other intracranial
hemorrhage, seen at baseline and day 7 will be graded using the Heidelberg Bleeding
Classification (HBC). Incident HT seen on follow-up CT scan is defined as new or progressive
HT. Progressive HT will be defined as any increase in the severity grade between the baseline
and follow-up scan. Two raters will rate the HT using the Heidelberg criteria.
RNA Analysis:
A blood sample will be drawn into a PAXgene tube for RNA analysis at the time of the baseline
CT. RNA will be isolated and measured by RNA sequencing and reverse transcription polymerase
chain reaction (RT-PCR). Genes different between patients who develop HT compared to those
without HT will be identified by analysis of variance adjusted for covariates as previously
described. A prediction model will be developed using the identified genes. The ability of
the developed gene model to predict HT will be compared to other factors associated with HT
including age, stroke severity, infarct volume.
Endpoints:
The primary study endpoint is the rate of incident (new or progressive) radiological HT. The
secondary endpoint is the rate of symptomatic HT, defined as intracerebral hemorrhage within
and beyond infarcted brain tissue with PH >1/3 the volume of the ischemic infarct (Class 2 in
HBC) associated with clinical deterioration (worsening of NIHSS score by ≥ 4 points) within
30 days of treatment initiation. Other secondary endpoints are recurrent ischemic stroke
within 90 days of randomization, recurrent sub-clinical infarcts on follow up CT at 7±2 days
post edoxaban initiation, systemic hemorrhagic complication rate within 90 days of
randomization, NIHSS at day 7 and 90, mRS score at day 7 and 90, favourable mRS at day 90,
and mortality within 90 days, quality of life at 90 days assessed by (EQ-5D) and Visual
Analog Scale (VAS), and ability of leukocyte RNA to predict HT.
Investigators will report serious adverse events (SAE) within the study period using
standardized event, resolution and association codes, and they will be reported to the local
Human Research Ethics Board.
Sample Size:
Based on previous open label studies of DOAC use in acute stroke, the rate of symptomatic HT
is likely to be nil, which is why we have made this a secondary endpoint. We have previously
demonstrated the rate of asymptomatic HT in serial imaging studies to be as lower as 3% in
CT-based studies and up to 13% in MRI based studies. There are no data related to the
difference in asymptomatic HT rates in patients randomized to early versus late DOAC
initiation. Our aim is to determine the event rates in these two groups with reasonable
precision.
A sample size of 150 patients, randomized 2:1 (≤5 days:6-14 days) will allow detection of an
asymptomatic hemorrhage rate of 3% (95% CI 0.6-8.5%) in the early treatment arm (n=100) and
4% (95% CI 0.5-13.7%) in the late treatment arm (n=50). Thus, we will have confidence
interval width of a maximum of 13.7%, allowing enough precision to demonstrate the safety of
early treatment. The rationale for adopting a 2:1 randomization approach is to increase the
precision around the estimate of safety in the early treatment arm, without substantively
losing power.