Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04698031 |
| Other study ID # |
NURC-021-20S |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
March 30, 2022 |
| Est. completion date |
May 30, 2025 |
Study information
| Verified date |
February 2024 |
| Source |
VA Office of Research and Development |
| Contact |
Calin I Prodan, MD |
| Phone |
(405) 456-1479 |
| Email |
calin.prodan[@]va.gov |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Silent brain infarctions (SBIs) are a manifestation of covert cerebrovascular disease,
without obvious clinical deficit, noted very often in patients presenting with a new stroke
or new transient ischemic attack. SBIs are linked to a significant increase in risk for
subsequent stroke and cognitive decline. However, no biomarker is currently available that
can predict the recurrence of these subclinical lesions. Coated-platelets are a measure of
platelet procoagulant potential significantly increased in patients with ischemic stroke or
transient ischemic attack compared to unaffected controls. Higher coated-platelet levels are
strongly associated with both the presence and number of SBIs. Among medications approved for
preventing stroke recurrence, we identified clopidogrel as a pharmacological agent leading to
a decrease in coated-platelet levels. In this project, we plan to evaluate if clopidogrel can
decrease the rate of occurrence of new silent brain infarctions. The result will enhance the
investigators understanding of the relationship between platelets and silent brain infarcts,
leading to improved health care delivery and also potential targets for novel preventive
pharmacological interventions.
Description:
Introduction:
Silent brain infarcts (SBIs) are a recently recognized, commonly noted and yet poorly
understood finding of cerebral infarction on imaging studies without a clinically apparent
neurological deficit. The availability of high resolution brain imaging such as MRI has made
the recognition and characterization of these covert markers of cerebrovascular disease
possible. SBIs, also referred to as silent strokes, are subcortical cavities or cortical
areas of gliosis presumed to be caused by previous infarction.
The prevalence of SBIs in the general population ranges between 8 and 28% in large
cardiovascular and aging studies performed in Europe and North America. A key finding has
been that prevalence rates are relatively low before age 65 with a gradual increase seen with
aging. Among vascular risk factors, hypertension has the strongest association with SBIs,
however other vascular risk factors, such as stroke, have been associated with increased
prevalence of these lesions. The overall prevalence of SBI far exceeds that of symptomatic
stroke and is estimated that for every symptomatic stroke there are approximately 10 SBIs.
Incidence data for SBIs are sparse, likely a reflection of the need for repeat imaging
studies. Incidence in the general population is estimated at 3% and 6.5% per year from large
population studies. A high incidence of SBIs has been reported following procedures such as
aortic valve replacement or carotid endarterectomy, likely directly related to these
procedures. Research data in a cohort of TIA patients who underwent initial MRI at the time
of the diagnosis and then repeat brain MRI one year after the index event showed a 37%
incidence of new SBIs.
There has been considerable evidence linking SBIs with an increased risk for subsequent
occurrence of stroke, development of cognitive decline and mortality, suggesting that SBIs
are precursors of more severe ischemic brain disease.
Coated-platelets are a class of activated platelets, detected only after simultaneous
stimulation with two agonists, thrombin and collagen, or thrombin and convulxin, a collagen
receptor agonist from tropical rattlesnake venom. In stroke-free controls, coated-platelets
represent approx. 30% of all platelets. Coated-platelet levels are increased in stroke
patients as compared to those with lacunar stroke or controls; higher coated-platelet levels
measured at the time of the clinical infarct correlate with an increased risk for recurrence
at 12 months while lower coated-platelet levels are related to the occurrence of very early
inpatient major hemorrhagic complications. These data support a role for platelet
procoagulant potential in the balance between thrombosis and hemorrhage.
Several investigations highlight the possibility that coated-platelets play a role in the
events preceding stroke. In asymptomatic carotid stenosis, patients with coated-platelet
levels 45.2% are at highest risk for incident stroke as compared to those with levels < 45.2
%. In SAH patients, delayed cerebral ischemia (ischemic strokes occurring days after the
initial hemorrhage) was linked to a steep increase in coated-platelet levels immediately
predating the infarct. Recent work in stroke patients found higher coated-platelet levels
significantly associated with the presence and number of SBIs.
Longitudinal data in stroke patients exploring the impact of medications used for secondary
stroke prevention identified clopidogrel as the only pharmacological agent leading to a
sustained decrease in coated-platelet levels after initiation of therapy. Aspirin,
anticoagulation therapy or statins did not lead to a similar effect.
Methods:
The goal of the investigators study is to evaluate the efficacy of clopidogrel on the
incidence of silent brain infarction in patients with stroke/TIA using a randomized,
double-blind aspirin-controlled clinical trial. The investigator's hypothesis is that
clopidogrel treatment will lead to decreased incidence of SBIs in patients with non-lacunar
stroke/TIA treated over a two-year period.
Consecutive eligible patients admitted with ischemic stroke or TIA to the Neurology service
qualifying for the study (see inclusion and exclusion criteria separately) will be randomized
to either clopidogrel or aspirin, stratified by sex. The study statisticians will create the
randomization sequence using randomly chosen block sizes of four or six and will implement
the sequence concealment. These doses are part of the recommended guidelines for secondary
stroke prevention and both medications are FDA approved for secondary stroke prevention.
All patients will be followed by the research team in conjunction with regularly scheduled
outpatient visits for up to one year independent of the current study. After the 12-month
time point, the investigators will maintain phone contact with each patient for an additional
12 months to decrease loss to follow-up. Prior to the 24-month time point, the PI/Research
Assistant will order a repeat non-contrast MRI for each patient.
Initial and repeat MRI images will be independently reviewed after the repeat scan is
completed at 24 months by two experienced stroke specialists while blinded to the
coated-platelet levels and treatment arm. The initial and repeat MRI will be compared for the
presence of new (interval) SBIs in order to determine SBI incidence.
SBIs will be identified on MRI studies, using a 1.5 Tesla magnet, based on published
guidelines as focal (ovoid or irregularly shaped), 3mm, cavitary lesions, displaying T1
hypointensity and T2 hyperintensity features, and hypointense on FLAIR sequences. In
addition, the cortical SBIs (10% of lesions) may also display some focal atrophic changes of
the cerebral cortex in the area surrounding the infarct. These lesions have a chronic
appearance, can be easily distinguished from acute ischemic changes through the use of DWI
and ADC images and have no corresponding, clinically apparent, cerebrovascular ischemic event
noted in the patient's history.
Using electronic medical records, the investigators will collect the following data:
prescription medicines, age, sex, race, ethnicity, past medical history, type of stroke,
National Institutes of Health Stroke Scale (NIHSS) score upon admission, results of
diagnostic studies performed for stroke, vascular risk factors (diabetes, hypertension,
large-artery artery disease, atrial fibrillation, prior stroke/TIA, hypercholesterolemia,
obesity, cardiac disease, aortic arch plaque, smoking, alcohol consumption), hematological
parameters (total platelet count, mean platelet volume, white blood cell count and
hemoglobin), and coagulation studies (PT, PTT and INR).
Because prior research linked interval development of SBIs with decline in cognitive
function, patients will be screened for cognitive impairment at discharge using the MoCA
test. Those with abnormal MoCA results (<26/30 points) will be referred to the Memory Loss
clinic for memory loss assessment, including neuropsychological testing. At the end to the
follow-up period repeat neuropsychological testing will be performed in individuals who were
evaluated initially and compared to the initial results. The investigators will also repeat
cognitive screening with MOCA in patients who scored within normal range initially, and those
with abnormal results at 24 months will undergo memory loss assessment.
Statistical analysis:
A target sample size of 152 participants (76 clopidogrel and 76 aspirin) over 1.5 years (8.4
patients/month) is sufficient to provide preliminary estimates of the effect size and
variation in efficacy, as well as feasibility information regarding the conduct of the
clinical trial. This calculation provides 80% power to detect a 65% reduction in the hazard
of SBI for those receiving clopidogrel versus aspirin, assuming a 2-sided 0.05 alpha level,
loss-to-follow-up and death rates of 10%, and follow-up for 24 months. Even if the effect
size observed in the clinical trial is not as large, the trial will still generate valuable
estimates of effect size and variation for efficacy, as well as feasibility information.
These estimates can be used to design a larger, more definitive clinical trial.
The time to incident SBI distribution will be compared between the clopidogrel and aspirin
arms using a log-rank test. Adverse event will be compared between the treatment groups using
a Chi-square test, or Fisher's exact test for rare events. Analyses will be based on the
intention-to-treat principle. A separate per-protocol analysis, analyzing data from all
patients who adhered to the study medication will be performed. No formal interim efficacy
analyses will be performed. Data quality, protocol implementation, retention and patient
adherence and adverse events will be summarized every six months. Statistical significance
will be set at p<0.05. A multiple imputation method will be used to impute missing data.
Anticipated findings:
The investigators anticipate that treatment with clopidogrel at standard dose for secondary
stroke prevention will lead to a significant decrease in the incidence of SBIs as compared to
treatment with aspirin. The current data will provide proof of concept for future larger
trials with more extended follow-up time that are able to also evaluate reduction on key
cardiovascular outcomes, such as stroke, myocardial infarction and sudden death. In addition,
key data regarding clinical and imaging features of patients with SBI and progression of
cognitive impairment will be obtained.
