Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial - Hemodynamics (CREST-H)
NCT ID: NCT03121209
Last Updated: 2025-09-26
Study Results
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Basic Information
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ACTIVE_NOT_RECRUITING
PHASE3
385 participants
INTERVENTIONAL
2018-01-18
2027-07-31
Brief Summary
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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.
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
PREVENTION
SINGLE
Study Groups
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Revascularization Arm (CEA or CAS)
These patients will have been randomized (via the parent trial, CREST-2) to receive intensive medical management as well as either Carotid Endarterectomy (CEA--if they are in the parent study Surgical trial) or Carotid Artery Stenting (CAS--if they are in the parent study Stenting trial).
Revascularization
Patients in this arm are randomized to CEA/CAS plus IMM
Intensive Medical Management (IMM) Arm
These patients will have been randomized (via the parent trial, CREST-2) to receive medical management only, which includes aspirin. high dose cholesterol lowering agent to a target LDL\<70, intensive blood pressure management to target \<130/80, smoking cessation, and diabetic control.
Intensive Medical Management (IMM) alone
Patients in this arm are randomized to intensive medical management (IMM) alone
Interventions
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Revascularization
Patients in this arm are randomized to CEA/CAS plus IMM
Intensive Medical Management (IMM) alone
Patients in this arm are randomized to intensive medical management (IMM) alone
Eligibility Criteria
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Inclusion Criteria
* age 35-86
Exclusion Criteria
* 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
35 Years
86 Years
ALL
No
Sponsors
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National Institute of Neurological Disorders and Stroke (NINDS)
NIH
Mayo Clinic
OTHER
University of Alabama at Birmingham
OTHER
University of Maryland
OTHER
University of California, Los Angeles
OTHER
Columbia University
OTHER
Responsible Party
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Randolph S. Marshall, MD
Professor of Neurology
Principal Investigators
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Randolph S Marshall, MD
Role: STUDY_CHAIR
Columbia University
Ronald M Lazar, PhD
Role: STUDY_DIRECTOR
University of Alabama at Birmingham
E Sander Connolly, MD
Role: STUDY_DIRECTOR
Columbia University
David S Liebeskind, MD
Role: STUDY_DIRECTOR
University of California, Los Angeles
Locations
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The University of Alabama at Birmingham
Birmingham, Alabama, United States
Huntsville Hospital/ Heart Center Research Alabama
Huntsville, Alabama, United States
St. Joseph's Hospital and Medical Center/ Barrow
Phoenix, Arizona, United States
University of Arizona
Tucson, Arizona, United States
Central Arkansas Veteran's Healthcare System
Little Rock, Arkansas, United States
Kaiser Permanente Los Angeles Medical Center
Los Angeles, California, United States
Keck Medical Center of University of Southern California
Los Angeles, California, United States
University of California at Los Angeles
Los Angeles, California, United States
Kaiser Permanente
San Diego, California, United States
University of California San Diego
San Diego, California, United States
San Francisco VA Medical Center
San Francisco, California, United States
Stanford University Medical Center
Stanford, California, United States
Yale New Haven Hospital
New Haven, Connecticut, United States
Morton Plant Hospital
Clearwater, Florida, United States
University of Florida Health at Shands
Gainesville, Florida, United States
Mayo Clinic Florida
Jacksonville, Florida, United States
University of Miami Hospital
Miami, Florida, United States
University of Chicago
Chicago, Illinois, United States
Northwestern University
Evanston, Illinois, United States
Mercy Health Riverside
Rockford, Illinois, United States
University of Iowa
Iowa City, Iowa, United States
Ochsner Health System
New Orleans, Louisiana, United States
Maine Medical Center
Portland, Maine, United States
University of Maryland VA
Baltimore, Maryland, United States
Adventist HealthCare/White Oak Medical Center
Gaithersburg, Maryland, United States
Michigan Vascular Center/McLaren-Flint
Flint, Michigan, United States
Minneapolis Clinic of Neurology, Ltd./ North Memorial Medical Center
Golden Valley, Minnesota, United States
University of Minnesota
Minneapolis, Minnesota, United States
Mayo Clinic Rochester
Rochester, Minnesota, United States
Mercy Hospital St Louis
St Louis, Missouri, United States
SUNY Buffalo
Buffalo, New York, United States
New York Presbyterian Columbia University Medical Center
New York, New York, United States
Weill Cornell Medical Center
New York, New York, United States
Novant Health Forsythe
Winston-Salem, North Carolina, United States
Wake Forest University Health Sciences
Winston-Salem, North Carolina, United States
Louis Stokes Cleveland VA Medical Center
Cleveland, Ohio, United States
University Hospitals Cleveland Medical Center
Cleveland, Ohio, United States
Ohio State Medical Center
Columbus, Ohio, United States
Ohio Health Research Institute
Columbus, Ohio, United States
UPMC Altoona
Altoona, Pennsylvania, United States
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States
UPMC Presbyterian University Hospital
Pittsburgh, Pennsylvania, United States
The Miriam Hospital/ Rhode Island Hospital
Providence, Rhode Island, United States
Medical University of South Carolina
Charleston, South Carolina, United States
North Central Heart Institute
Sioux Falls, South Dakota, United States
Tennova Healthcare/ Turkey Creek Medical Center
Knoxville, Tennessee, United States
Houston Methodist Hospital
Houston, Texas, United States
Intermountain Medical Center
Murray, Utah, United States
University of Utah Hospitals and Clinics
Salt Lake City, Utah, United States
University of Virginia Health System
Charlottesville, Virginia, United States
Inova Fairfax Health Care
Falls Church, Virginia, United States
Overlake Hospital Medical Center
Bellevue, Washington, United States
University of Washington Medicine-Harborview Medical Center
Seattle, Washington, United States
VA Puget Sound Health Care System
Seattle, Washington, United States
Gundersen Clinic, Ltd
La Crosse, Wisconsin, United States
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States
Vancouver General Hospital
Vancouver, British Columbia, Canada
St. Boniface Hospital
Winnipeg, Manitoba, Canada
Countries
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References
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Marshall RS, Lazar RM, Liebeskind DS, Connolly ES, Howard G, Lal BK, Huston J 3rd, Meschia JF, Brott TG. Carotid revascularization and medical management for asymptomatic carotid stenosis - Hemodynamics (CREST-H): Study design and rationale. Int J Stroke. 2018 Dec;13(9):985-991. doi: 10.1177/1747493018790088. Epub 2018 Aug 22.
Marshall RS, Liebeskind DS, Iii JH, Edwards LJ, Howard G, Meschia JF, Brott TG, Lal BK, Heck D, Lanzino G, Sangha N, Kashyap VS, Morales CD, Cotton-Samuel D, Rivera AM, Brickman AM, Lazar RM. Cortical Thinning in High-Grade Asymptomatic Carotid Stenosis. J Stroke. 2023 Jan;25(1):92-100. doi: 10.5853/jos.2022.02285. Epub 2023 Jan 3.
Other Identifiers
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AAAR5617
Identifier Type: -
Identifier Source: org_study_id
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