Clinical trial NCT03121209: Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial - Hemodynamics (CREST-H)
Official title: Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial - Hemodynamics
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Internal Carotid Artery Stenosis
Cognitive Impairment
Lead sponsor: Columbia University
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
name: Mayo Clinic
name: University of Alabama at Birmingham
name: University of Maryland
name: University of California, Los Angeles
First posted: 2017-04-20
Enrollment: 385
Sex: ALL
Minimum age (years): 35
Maximum age (years): 86
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase 3 prospective blinded outcome randomized clinical trial
Primary purpose: PREVENTION

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Cognitive score at 1 year
timeFrame: 1 year
Secondary outcomes:
measure: MRI-determined silent infarcts present at 1 year that were not present at baseline.
timeFrame: 1 year
measure: Change from baseline of White matter hyperintensity (WMH) volume as measured by T2 FLAIR sequence on brain MRI.
timeFrame: 1 year
Other outcomes:
measure: Cognitive score beyond 1 year
timeFrame: 2, 3, and 4 years
measure: Correlation between change in cognition at 1 year, as measured in Outcome 1, and change in brain blood flow at 1 year as measured by time-to-peak (TTP) perfusion-weighted imaging (PWI) by MRI or computed tomography (CT).
timeFrame: 1 year
measure: Correlation of between change in cognition at 1 year and change in brain blood flow using other MRI PWI markers (CBF, CBV, Tmax).
timeFrame: 1 year
Locations:
city: Birmingham
country: United States
facility: The University of Alabama at Birmingham
state: Alabama
city: Huntsville
country: United States
facility: Huntsville Hospital/ Heart Center Research Alabama
state: Alabama
city: Phoenix
country: United States
facility: St. Joseph's Hospital and Medical Center/ Barrow
state: Arizona
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Little Rock
country: United States
facility: Central Arkansas Veteran's Healthcare System
state: Arkansas
city: Los Angeles
country: United States
facility: Kaiser Permanente Los Angeles Medical Center
state: California
city: Los Angeles
country: United States
facility: Keck Medical Center of University of Southern California
state: California
city: Los Angeles
country: United States
facility: University of California at Los Angeles
state: California
city: San Diego
country: United States
facility: Kaiser Permanente
state: California
city: San Diego
country: United States
facility: University of California San Diego
state: California
city: San Francisco
country: United States
facility: San Francisco VA Medical Center
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: New Haven
country: United States
facility: Yale New Haven Hospital
state: Connecticut
city: Clearwater
country: United States
facility: Morton Plant Hospital
state: Florida
city: Gainesville
country: United States
facility: University of Florida Health at Shands
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic Florida
state: Florida
city: Miami
country: United States
facility: University of Miami Hospital
state: Florida
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Evanston
country: United States
facility: Northwestern University
state: Illinois
city: Rockford
country: United States
facility: Mercy Health Riverside
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: New Orleans
country: United States
facility: Ochsner Health System
state: Louisiana
city: Portland
country: United States
facility: Maine Medical Center
state: Maine
city: Baltimore
country: United States
facility: University of Maryland VA
state: Maryland
city: Gaithersburg
country: United States
facility: Adventist HealthCare/White Oak Medical Center
state: Maryland
city: Flint
country: United States
facility: Michigan Vascular Center/McLaren-Flint
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Mercy Hospital St Louis
state: Missouri
city: Buffalo
country: United States
facility: SUNY Buffalo
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: New York Presbyterian Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical Center
state: New York
city: Winston-Salem
country: United States
facility: Novant Health Forsythe
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Cleveland
country: United States
facility: Louis Stokes Cleveland VA Medical Center
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State Medical Center
state: Ohio
city: Columbus
country: United States
facility: Ohio Health Research Institute
state: Ohio
city: Altoona
country: United States
facility: UPMC Altoona
state: Pennsylvania
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Presbyterian University Hospital
state: Pennsylvania
city: Providence
country: United States
facility: The Miriam Hospital/ Rhode Island Hospital
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Sioux Falls
country: United States
facility: North Central Heart Institute
state: South Dakota
city: Knoxville
country: United States
facility: Tennova Healthcare/ Turkey Creek Medical Center
state: Tennessee
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Hospitals and Clinics
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Falls Church
country: United States
facility: Inova Fairfax Health Care
state: Virginia
city: Seattle
country: United States
facility: University of Washington Medicine-Harborview Medical Center
state: Washington
city: Seattle
country: United States
facility: VA Puget Sound Health Care System
state: Washington
city: La Crosse
country: United States
facility: Gundersen Clinic, Ltd
state: Wisconsin
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: St. Boniface Hospital
state: Manitoba
Study officials:
affiliation: Columbia University
name: Randolph S Marshall, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.