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

Cognitive Impairment Clinical Trial

— CREST-H  

Official title:

Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial - Hemodynamics

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03121209
• Other study ID #: AAAR5617
• Secondary ID: 1R01NS097876-01A
• Status: Recruiting
• Phase: Phase 3
• Start date: January 18, 2018
• Est. completion date: July 31, 2027

Study information

• Verified date: April 2024
• Source: Columbia University
• Contact: Kevin Slane, BA
• Phone: 212-342-1152
• Email: kjs4[@]cumc.columbia.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 385
• Est. completion date: July 31, 2027
• Est. primary completion date: January 31, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 35 Years to 86 Years

Eligibility

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

Related Conditions & MeSH terms

• Carotid Stenosis
• Cognitive Impairment
• Constriction, Pathologic
• Internal Carotid Artery Stenosis

Intervention

Procedure:
• Revascularization
Patients in this arm are randomized to CEA/CAS plus IMM

Other:
• Intensive Medical Management (IMM) alone
Patients in this arm are randomized to intensive medical management (IMM) alone

Locations

Country	Name	City	State
Canada	Vancouver General Hospital	Vancouver	British Columbia
Canada	St. Boniface Hospital	Winnipeg	Manitoba
United States	UPMC Altoona	Altoona	Pennsylvania
United States	University of Maryland VA	Baltimore	Maryland
United States	The University of Alabama at Birmingham	Birmingham	Alabama
United States	SUNY Buffalo	Buffalo	New York
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Virginia Health System	Charlottesville	Virginia
United States	University of Chicago	Chicago	Illinois
United States	Morton Plant Hospital	Clearwater	Florida
United States	Louis Stokes Cleveland VA Medical Center	Cleveland	Ohio
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	Ohio Health Research Institute	Columbus	Ohio
United States	Ohio State Medical Center	Columbus	Ohio
United States	Northwestern University	Evanston	Illinois
United States	Inova Fairfax Health Care	Falls Church	Virginia
United States	Michigan Vascular Center/McLaren-Flint	Flint	Michigan
United States	University of Florida Health at Shands	Gainesville	Florida
United States	Adventist HealthCare/White Oak Medical Center	Gaithersburg	Maryland
United States	Houston Methodist Hospital	Houston	Texas
United States	Huntsville Hospital/ Heart Center Research Alabama	Huntsville	Alabama
United States	University of Iowa	Iowa City	Iowa
United States	Mayo Clinic Florida	Jacksonville	Florida
United States	Tennova Healthcare/ Turkey Creek Medical Center	Knoxville	Tennessee
United States	Gundersen Clinic, Ltd	La Crosse	Wisconsin
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	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	University of Miami Hospital	Miami	Florida
United States	University of Minnesota	Minneapolis	Minnesota
United States	Yale New Haven Hospital	New Haven	Connecticut
United States	Ochsner Health System	New Orleans	Louisiana
United States	Columbia University Medical Center	New York	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	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	St. Joseph's Hospital and Medical Center/ Barrow	Phoenix	Arizona
United States	UPMC Presbyterian University Hospital	Pittsburgh	Pennsylvania
United States	Maine Medical Center	Portland	Maine
United States	The Miriam Hospital/ Rhode Island Hospital	Providence	Rhode Island
United States	Mayo Clinic Rochester	Rochester	Minnesota
United States	Mercy Health Riverside	Rockford	Illinois
United States	Mercy Hospital St Louis	Saint Louis	Missouri
United States	University of Utah Hospitals and Clinics	Salt Lake City	Utah
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	University of Washington Medicine-Harborview Medical Center	Seattle	Washington
United States	VA Puget Sound Health Care System	Seattle	Washington
United States	North Central Heart Institute	Sioux Falls	South Dakota
United States	Stanford University Medical Center	Stanford	California
United States	University of Arizona	Tucson	Arizona
United States	Novant Health Forsythe	Winston-Salem	North Carolina
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (6)

Lead Sponsor	Collaborator
Columbia University	Mayo Clinic, National Institute of Neurological Disorders and Stroke (NINDS), University of Alabama at Birmingham, University of California, Los Angeles, University of Maryland

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (2)

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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Cognitive score beyond 1 year	Change in composite Z-score from baseline to 2-4 years on the CREST-2 cognitive battery. Range: -2.0 to 2.0. Positive Z-score change indicates improvement; negative Z-score change indicates worsening.	2, 3, and 4 years
Other	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).	Time-to-peak (TTP) perfusion weighted imaging (PWI) will be derived using a semi-automated software platform that computes quantitative perfusion maps.	1 year
Other	Correlation of between change in cognition at 1 year and change in brain blood flow using other MRI PWI markers (CBF, CBV, Tmax).	CBF, CBV, and Tmax will be derived using a semi-automated software platform that computes quantitative perfusion maps.	1 year
Primary	Cognitive score at 1 year	Change in composite cognitive Z-score at 1 year will be computed from the cognitive battery of the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2; NCT02089217). Range: -2.0 to 2.0. Positive Z-score change indicates improvement; negative Z-score change indicates worsening.	1 year
Secondary	MRI-determined silent infarcts present at 1 year that were not present at baseline.	A neuroradiology study investigator assesses for new silent infarcts as defined by any non-confluent hyperintense lesion >3mm on T2 FLAIR sequence on 1-year MRI not present on baseline T2 FLAIR MRI	1 year
Secondary	Change from baseline of White matter hyperintensity (WMH) volume as measured by T2 FLAIR sequence on brain MRI.	A neuroradiology study investigator assesses for change in White matter hyperintensity (WMH) volume as defined by confluent periventricular high intensity lesions on T2 Fluid Attenuated Inversion Recovery (FLAIR) imaging.	1 year