Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial - Hemodynamics (CREST-H)
Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial - Hemodynamics (CREST-H)
We aim to determine whether cognitive impairment attributable to cerebral hemodynamic
 impairment in patients with high-grade asymptomatic carotid artery stenosis is reversible
 with restoration of flow. To accomplish this aim CREST-H will add on to the NINDS-sponsored
 CREST-2 trial (parallel, outcome-blinded Phase 3 clinical trials for patients with
 asymptomatic high-grade carotid artery stenosis which will compare carotid endarterectomy
 plus intensive medical management (IMM) versus IMM alone (n=1,240), and carotid artery
 stenting plus IMM versus IMM alone (n=1,240) to prevent stroke and death).

 CREST-H addresses the intriguing question of whether cognitive impairment can be reversed
 when it arises from abnormal cerebral hemodynamic perfusion in a hemodynamically impaired
 subset of the CREST-2 -randomized patients. We will enroll 500 patients from CREST-2, all of
 whom receive cognitive assessments at baseline and yearly thereafter. We anticipate
 identifying 100 patients with hemodynamic impairment as measured by an inter-hemispheral MRI
 perfusion "time to peak" (TTP) delay on the side of stenosis. Among those who are found to be
 hemodynamically impaired and have baseline cognitive impairment, the cognitive batteries at
 baseline and at 1 year will determine if those with flow failure who are randomized to a
 revascularization arm in CREST-2 will have better cognitive outcomes than those in the
 medical-only arm compared with this treatment difference for those who have no flow failure.

 We hypothesize that hemodynamically significant "asymptomatic" carotid disease may represent
 one of the few examples of treatable causes of cognitive impairment. If cognitive decline can
 be reversed in these patients, then we will have established a new indication for carotid
 revascularization independent of the risk of recurrent stroke.
CREST-H sites will be drawn from actively-enrolling CREST-2 centers. The additional
 information obtained in CREST-H in this protocol will be the MR imaging, which will be done
 at baseline for all patients enrolled in CREST-H, and at 1 year for those with hemodynamic
 impairment at baseline. The protocol will require an unblinded investigator at each CREST-H
 site who will order and obtain the study-related MRI sequences, upload de-identified image
 files to the CREST-2 central imaging site at U Maryland, and maintain blinding of the
 hemodynamic imaging data for their site (see Blinding below). Image analysis will be done at
 UCLA (for perfusion studies) and at Mayo Rochester for structural scans -- silent infarcts,
 WMH and microbleeds. Data management and statistical analysis will be done at UAB, which
 serves this role for CREST-2.

 Cognitive Assessment.

 CREST-H will use existing CREST-2 cognitive assessment infrastructure -- the Survey Research
 Unit at University of Alabama Birmingham. Added to the current CREST-2 battery is the Oral
 Trail Making A & B as an additional measure of executive function, which will be administered
 to every CREST-2 patient, regardless of their participation in CREST-H. Cognitive assessments
 in CREST-H must take place prior to revascularization or within two weeks after assignment to
 medical therapy alone. Testing in CREST-2 is repeated at 44 days, and every year thereafter
 up to 4 years. At each test interval, a composite (mean) Z-score is derived from published
 normative samples for each test outcome. The CREST-H primary outcome will be at 1 year in
 which the change in the composite Z-score from baseline will be calculated. Covariates will
 include age, education and depression. The test battery will be administered the same way for
 all CREST-2 and CREST-H enrolled patients. The cognitive domains being assessed in CREST-2/H
 are entirely consistent with those encompassed within the NINDS Common Data Elements (CDE).

 Imaging protocol.

 Multimodal MRI, including routine parenchymal sequences and PWI utilizing dynamic
 susceptibility contrast technique, will be acquired at each participating CREST H site.
 Imaging will take place within 14 days after CREST-H enrollment and prior to any CREST 2
 intervention for those randomized to CEA or CAS.

 Standardized contrast agent injection protocol, appropriate preparation, and IV setup is used
 to ensure good scan quality. An antecubital vein IV catheter of 18-20 gauge is required. A
 test injection will be performed with approximately 10 ml of normal saline solution.

 MRI image acquisition DWI/ADC (b=0, 1000 s/mm2 applied in each of three principal gradient
 directions), FLAIR, high-resolution T1, and GRE sequences will be acquired on 1.5-3.0 T
 scanners equipped with echo-planar imaging capability, using standard clinical protocols at
 participating CREST-H sites Total scanning time will be approximately 40 minutes. PWI
 acquisition protocol will be standardized across all CREST-H sites, using sequential
 T2*-weighted (gradient echo) EPI time sequence scanning. A modified 2-phase contrast
 injection scheme will be used to perform CEMRA and DSC perfusion imaging, without need for
 additional contrast.

 Perfusion imaging analysis.

 PWI source images will be sent to the core laboratory at UCLA and processed with the
 OleaSphere software platform, using deconvolution of tissue and arterial signals in an
 expedited manner, yielding standardized data regardless of the acquisition system at each
 site. Hemodynamic impairment is defined as TTP >2 sec in the middle cerebral artery and
 anterior cerebral artery territories of the ipsilateral hemisphere to the carotid lesion
 compared with the same territory in the opposite hemisphere. Longitudinal analyses will
 investigate the change in the TTP >2 sec lesion at 1 year comparing the revascularization
 versus the medical only arm. Continuous values for this volumetric change will be used to
 calculate the correlation between degree of cognitive change and degree of perfusion change.
 The continuous Tmax variable, as well as standard perfusion parameters of CBV, CBF Tmax, and
 MTT will be analyzed on the serial imaging studies in each case. Co-registered, voxel-based
 changes in serial perfusion values will also be explored with multiparametric (e.g. CBV, CBF,
 Tmax, MTT) values.

 Image de-identification and blinding.

 All MR image files will be de-identified under the supervision of an unblinded Investigator
 (UI) at each institution and uploaded to the CREST-2 Imaging Core site at U Maryland. In
 order to assure that the PWI scan information from CREST-H does not compromise the integrity
 of the parent trial, the results of the perfusion scan will be blinded to the investigator
 team.

 Image transfer.

 Participating sites will utilize the same file transfer protocol (ftp) to transfer images to
 U Maryland for CREST-H as is already established for CREST-2. The images will be stored in a
 HIPAA-compliant, firewall protected server within the U Maryland archival system. A CREST-2
 dedicated ftp linkage between the VIC at U Maryland and UCLA; and the VIC at U Maryland and
 Mayo-Rochester will be utilized to make each perfusion image file available for download by
 UCLA (Liebeskind lab) and each structural image (DWI, FLAIR, GRE) by Mayo-Rochester (Huston
 lab).

 MRI structural analysis.

 Structural MRI analysis at Mayo-Rochester will utilize NIH NINDS Common Data Elements
 developed for the CREST-2 grant. The following definitions apply:

 1. silent infarct --- non-confluent hyperintense lesion >1mm on FLAIR sequence on 1-year
 MRI not present on baseline FLAIR MRI.

 2. Cerebral microbleed - hypointense 1-2mm non-confluent lesion on baseline GRE sequence.

 3. WMH volume -- White matter hyperintensity volume refers to confluent periventricular
 high intensity lesions on FLAIR imaging, and will be derived using an automated T2 WMH
 quantification at the Huston lab.

 Data from image analysis (TTP delay, WMHV, silent infarct count, microbleed count) performed
 at UCLA and Mayo-Rochester will be entered electronically on CREST-H data forms via the
 CREST-2 SDCC website at UAB, where it will be stored on a separate webpage linked to the rest
 of the CREST-2 data, including baseline and yearly cognitive assessments. The electronic data
 entry system (eDES) for CREST-2 is a mature system, successfully reviewed by FDA audit in
 other studies, providing standard approaches for entry-confirmation-locking of data forms,
 and supporting range and validity checking for data provided.

 . Analysis.

 Specific Aim 1. To determine whether cognition can be improved by revascularization among a
 subset of CREST-2 patients with hemodynamic impairment at baseline.

 The primary hypothesis is to assess if the magnitude of the treatment differences
 (revascularization versus medical management alone) differs between those with flow failure
 compared to those without flow failure using the Z-scored cognitive outcomes (C0, C(1). That
 is, the primary hypothesis is an interaction hypothesis that will be assessed using linear
 regression, specifically: (C1 - C0) = β0 + β1T + β2F + β3TF + β4C0 + (other covariates),
 where C1 is the cognitive z-score at year 1, C0 the cognitive z-score at baseline, T the
 treatment indicator variable, F the flow failure indicator variable, and βi the regression
 parameters to be estimated. The parameter of interest for the primary hypothesis is then β3
 that would assess if the magnitude of treatment difference in the change in cognitive score
 between baseline and 1-year is similar for those with versus without flow failure.

 Secondary Aims: To determine if the number of silent infarcts and white matter hyperintensity
 volume at 1 year is different between the revascularization and the medical-only arms.

 For the secondary aims we will calculate the number of new silent cerebral infarctions
 occurring over the first year, and the change in the WMH volume. The approach for analysis of
 the number of new silent infarcts will depend on the average number and distribution of the
 number of new infarcts. The analytic approach will be linear regression if the number of new
 infarcts is large (considered more likely the case), or Poisson Regression if the number is
 smaller (considered less likely the case). The analysis of the change in WMH will use a
 linear regression approach.
Inclusion Criteria:

 -  Enrolled and randomized into CREST-2 (parent study)

 -  Inclusion criteria for CREST-2

 -  age 35-86

 Exclusion Criteria (in addition to the exclusion criteria for CREST-2):

 -  unable to undergo MRI (e.g. metal in body, pacemaker)

 -  known allergy gadolinium contrast dye

 -  pre-existing diagnosis of dementia

 -  contralateral ICA stenosis >70% by MRA, CTA or Doppler ultrasound

 -  history of severe head trauma

 -  major depression

 -  education less than 8 years