Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial - Hemodynamics (CREST-H)

Last updated: July 12, 2024
Sponsor: Columbia University
Overall Status: Active - Not Recruiting

Phase

3

Condition

Carotid Artery Disease

Mental Disability

Mild Cognitive Impairment

Treatment

Intensive Medical Management (IMM) alone

Revascularization

Clinical Study ID

NCT03121209
AAAR5617
1R01NS097876-01A1
  • Ages 35-86
  • All Genders

Study Summary

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 385 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.

Eligibility Criteria

Inclusion

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

Study Design

Total Participants: 385
Treatment Group(s): 2
Primary Treatment: Intensive Medical Management (IMM) alone
Phase: 3
Study Start date:
January 18, 2018
Estimated Completion Date:
July 31, 2027

Study Description

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 or CT 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 recommend 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 1 year, 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 by a blinded assessor 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 or CT perfusion imaging will be performed at baseline on every study subject.

Multimodal MRI, including routine parenchymal sequences and PWI utilizing dynamic susceptibility contrast technique, will be acquired at each participating CREST H site who have been approved for this imaging modality. CT perfusion, using iodinated contrast, will be used as an alternative PWI image for sites approved for this modality. 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.

CT perfusion imaging will follow the protocol outlined in the updated Imaging MOP for CREST-H. The CT perfusion study is identical to the clinical CTP protocol used for acute stroke imaging in most institutions.

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 >1.25 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 >1.25 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 with MR imaging. 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 or CT 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.

Connect with a study center

  • Vancouver General Hospital

    Vancouver, British Columbia V5Z 1M9
    Canada

    Site Not Available

  • St. Boniface Hospital

    Winnipeg, Manitoba MB R2H 2A6
    Canada

    Site Not Available

  • The University of Alabama at Birmingham

    Birmingham, Alabama 35294
    United States

    Site Not Available

  • Huntsville Hospital/ Heart Center Research Alabama

    Huntsville, Alabama 35801
    United States

    Site Not Available

  • St. Joseph's Hospital and Medical Center/ Barrow

    Phoenix, Arizona 85013
    United States

    Site Not Available

  • University of Arizona

    Tucson, Arizona 85724
    United States

    Site Not Available

  • Central Arkansas Veteran's Healthcare System

    Little Rock, Arkansas 72143
    United States

    Site Not Available

  • Kaiser Permanente Los Angeles Medical Center

    Los Angeles, California 90027
    United States

    Site Not Available

  • Keck Medical Center of University of Southern California

    Los Angeles, California 90033
    United States

    Site Not Available

  • University of California at Los Angeles

    Los Angeles, California 90095
    United States

    Site Not Available

  • Kaiser Permanente

    San Diego, California 92123
    United States

    Site Not Available

  • University of California San Diego

    San Diego, California 92182
    United States

    Site Not Available

  • San Francisco VA Medical Center

    San Francisco, California 94121
    United States

    Site Not Available

  • Stanford University Medical Center

    Stanford, California 94305
    United States

    Site Not Available

  • Yale New Haven Hospital

    New Haven, Connecticut 06520
    United States

    Site Not Available

  • Morton Plant Hospital

    Clearwater, Florida 33756
    United States

    Site Not Available

  • University of Florida Health at Shands

    Gainesville, Florida 32610
    United States

    Site Not Available

  • Mayo Clinic Florida

    Jacksonville, Florida 322224
    United States

    Site Not Available

  • University of Miami Hospital

    Miami, Florida 33136
    United States

    Site Not Available

  • University of Chicago

    Chicago, Illinois 60637
    United States

    Site Not Available

  • Northwestern University

    Evanston, Illinois 60208
    United States

    Site Not Available

  • Mercy Health Riverside

    Rockford, Illinois 61114
    United States

    Site Not Available

  • University of Iowa

    Iowa City, Iowa 52242
    United States

    Site Not Available

  • Ochsner Health System

    New Orleans, Louisiana 70121
    United States

    Site Not Available

  • Maine Medical Center

    Portland, Maine 04102
    United States

    Site Not Available

  • University of Maryland VA

    Baltimore, Maryland 21201
    United States

    Site Not Available

  • Adventist HealthCare/White Oak Medical Center

    Gaithersburg, Maryland 20878
    United States

    Site Not Available

  • Michigan Vascular Center/McLaren-Flint

    Flint, Michigan 48532
    United States

    Site Not Available

  • University of Minnesota

    Minneapolis, Minnesota 55455
    United States

    Site Not Available

  • Mayo Clinic Rochester

    Rochester, Minnesota 55905
    United States

    Site Not Available

  • Mercy Hospital St Louis

    Saint Louis, Missouri 63141
    United States

    Site Not Available

  • SUNY Buffalo

    Buffalo, New York 14203
    United States

    Site Not Available

  • Columbia University Medical Center

    New York, New York 10032
    United States

    Site Not Available

  • New York Presbyterian Columbia University Medical Center

    New York, New York 10032
    United States

    Site Not Available

  • Weill Cornell Medical Center

    New York, New York 10065
    United States

    Site Not Available

  • Novant Health Forsythe

    Winston-Salem, North Carolina 27103
    United States

    Site Not Available

  • Wake Forest University Health Sciences

    Winston-Salem, North Carolina 27157
    United States

    Site Not Available

  • Louis Stokes Cleveland VA Medical Center

    Cleveland, Ohio 44106
    United States

    Site Not Available

  • University Hospitals Cleveland Medical Center

    Cleveland, Ohio 44106
    United States

    Site Not Available

  • Ohio Health Research Institute

    Columbus, Ohio 43214,
    United States

    Site Not Available

  • Ohio State Medical Center

    Columbus, Ohio 43210
    United States

    Site Not Available

  • UPMC Altoona

    Altoona, Pennsylvania 16601
    United States

    Site Not Available

  • Hospital of the University of Pennsylvania

    Philadelphia, Pennsylvania 19104
    United States

    Site Not Available

  • UPMC Presbyterian University Hospital

    Pittsburgh, Pennsylvania 15213
    United States

    Site Not Available

  • The Miriam Hospital/ Rhode Island Hospital

    Providence, Rhode Island 02906
    United States

    Site Not Available

  • Medical University of South Carolina

    Charleston, South Carolina 29425
    United States

    Site Not Available

  • North Central Heart Institute

    Sioux Falls, South Dakota 57108
    United States

    Site Not Available

  • Tennova Healthcare/ Turkey Creek Medical Center

    Knoxville, Tennessee 37934
    United States

    Site Not Available

  • Houston Methodist Hospital

    Houston, Texas 77030
    United States

    Site Not Available

  • Intermountain Medical Center

    Murray, Utah 84107
    United States

    Site Not Available

  • University of Utah Hospitals and Clinics

    Salt Lake City, Utah 84132
    United States

    Site Not Available

  • University of Virginia Health System

    Charlottesville, Virginia 22908
    United States

    Site Not Available

  • Inova Fairfax Health Care

    Falls Church, Virginia 22042
    United States

    Site Not Available

  • Overlake Hospital Medical Center

    Bellevue, Washington 98004
    United States

    Site Not Available

  • University of Washington Medicine-Harborview Medical Center

    Seattle, Washington 98104
    United States

    Site Not Available

  • VA Puget Sound Health Care System

    Seattle, Washington 98108
    United States

    Site Not Available

  • Gundersen Clinic, Ltd

    La Crosse, Wisconsin 54601
    United States

    Site Not Available

  • University of Wisconsin Hospital and Clinics

    Madison, Wisconsin 53792
    United States

    Site Not Available

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