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IMaging Della PLAcca Carotidea (IMPLAC)

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT03333330
First Posted: November 6, 2017
Last Update Posted: November 8, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Enrico Ammirati, Università Vita-Salute San Raffaele
  Purpose

Background-White matter hyperintensities (WMH), patchy areas of hyperintense signal on T2-weighted or Fluid Attenuated Inversion Recovery sequences on brain magnetic resonance imaging (MRI), are believed to reflect cerebral burden of ischemic damage and are associated to incident stroke, dementia and eventually mortality in otherwise healthy subjects. Also brain atrophy has been related with presence of carotid atherosclerosis and vascular cognitive impairment. Carotid atherosclerosis may contribute to the genesis of WMH. A recent meta-analysis by our group comprising 5306 subjects was able to demonstrate an association between the presence of carotid atherosclerosis and WMH (odds ratio, OR, 1.42, 95% confidence interval [CI] 1.22-1.66).

Objective-To evaluate the relation between carotid artery plaque characteristics, cardiovascular risk factors and brain atrophy/WMH burden analyzed quantitatively as number and volume of lesions and as brain volumes, and progression over 18 months of follow up in subjects asymptomatic for cerebrovascular disease with a carotid artery stenosis <70%.


Condition Intervention Phase
Carotid Artery Plaque Atherosclerosis Ischemic Stroke Drug: Visipaque 320 and SonoVue Phase 3

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Non Invasive Vascular Imaging Combined With Systemic Biomarkers and Brain Magnetic Resonance Imaging for Identification of Asymptomatic Patients With Unstable Carotid Atherosclerosis

Resource links provided by NLM:


Further study details as provided by Enrico Ammirati, Università Vita-Salute San Raffaele:

Primary Outcome Measures:
  • Changes of total cerebral white matter lesions from baseline (T2-weight lesions, in terms of number and total volumes indexed to the total brain volume) [ Time Frame: 18 months ]
    We expect that asymptomatic patients with carotid atherosclerosis with characteristics of vulnerability of the plaque can develop a larger burden of silent cerebral ischemic lesions along the timeframe of the study. We are going to compare patients with progression compared those without significant progression or no progression.


Secondary Outcome Measures:
  • Changes of total brain volume and grey matter volume from baseline [ Time Frame: 18 months ]
    We expect that asymptomatic patients with carotid atherosclerosis with characteristics of vulnerability of the plaque can develop atrophy of the total brain volume or/and grey matter volume along the timeframe of the study. We are going to compare patients with progression of atrophy compared those without significant progression or no progression.

  • Changes of ipsilateral cerebral white matter lesions from baseline (T2-weight lesions, in terms of number and total volumes indexed to the total brain volume) [ Time Frame: 18 months ]
    We expect that asymptomatic patients with carotid atherosclerosis with characteristics of vulnerability of the plaque can develop a larger burden of silent cerebral ischemic lesions along the timeframe of the study. We are going to compare patients with progression compared those without significant progression or no progression.

  • Changes of the carotid total plaque area and extent of CEUS positive plaques [ Time Frame: 18 months ]
    We expect that asymptomatic patients with carotid atherosclerosis with characteristics of vulnerability of the plaque based on CEUS positive plaques and based on cardiovascular risk factors and ongoing treatments can develop a larger extent of total plaque area or/and extent of CEUS positive plaque.

  • Compare the esteem of the degree and the characteristics of the main plaque with standard Duplex scan versus CEUS using contrast enhanced carotid CT scan as gold standard [ Time Frame: at baseline ]
    We expect that CEUS can be superior compared with standard Duplax scan of the carotid artery in the evaluation of degree of stenosis and presence of irregularity on the surface of the plaque.


Other Outcome Measures:
  • Specific biomarkers (specific T-cell subsets and monocytic subsets and other cytokines) can be associated with WMH and brain atrophy at base line and at follow up (biomarkers to identify progression of WMHs and brain atrophy) [ Time Frame: 18 months ]
    We expect in particular that circulating HLA-DR+CD4+T cells and CD14+CD16- monocytes will be increased in patients with WMH and/or brain atrophy progression


Enrollment: 75
Actual Study Start Date: April 2012
Study Completion Date: October 2017
Primary Completion Date: October 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Carotid imaging with Visipaque 320 and SonoVue

Patients undergo to brain MRI, carotid contrast-enhanced CTA, duplex ultrasound, CEUS, blood sampling, clinical structured interview.

Intervention is related to the administration of contrast agents:

Visipaque 320 for contrast-enhanced CTA, and SonoVue for CEUS

Drug: Visipaque 320 and SonoVue

Intervention is related to the administration of contrast agents:

Iodixanol, 320 mg of iodine per millilitre, Visipaque 320 (GE Healthcare, Milwaukee, WI, USA) for contrast-enahnced CTA, Sodium hexafluoride (SonoVue, Bracco Imaging, Milan, Italy) for CEUS

Other Name: Contrast agents

Detailed Description:
  • Ischemic stroke and vascular cognitive impairment pose a massive clinical, social and economic burden. Disruption of carotid plaques, often non-obstructive, with subsequent thrombosis and distal embolization is one of leading pathogenetic mechanism of ischemic stroke. The widespread use of brain magnetic resonance imaging (MRI) has enabled an increased recognition, especially in elderly subjects, of cerebral alterations in apparently healthy individuals.
  • Carotid plaque may be causative in the development of white matter hyperintensities (WMH, patchy areas of signal hyperintensity on T2-weighted and/or fluid attenuated inversion recovery -FLAIR- sequences), silent brain infarcts (SBI) and eventually brain atrophy.
  • The hypothesis of the investigators is that carotid plaques with features of vulnerability detected by multimodality imaging (including standard ultrasound, contrast enhanced ultrasound -CEUS-, contrast enhanced CT angiography) and larger extent of atherosclerotic process, even if determining only an intermediate degree of stenosis, could bear a more rapid progression of silent WMH and brain atrophy.
  • Carotid CT and CEUS allow fast and reproducible evaluation of plaque size and morphology, alongside with functional parameters. Plaque density and positive remodelling on CT have been repeatedly associated to histological features of plaque vulnerability. At the same time, when compared to standard duplex evaluation, CEUS allowed a better imaging definition of plaque margins and extension, and to evaluate intraplaque neovascularization. The latter associates with local inflammation and plaque vulnerability, and might give rise to plaque hematomas, which are among the substrates for lesion progression and for the development of atherothrombosis.
  • In the initial phase of the study also hybrid imaging with positron tomography and computed tomography angiography (PET/CTA) using 11C-PK11195 was used to detect and quantify intraplaque inflammation in humans.(7) C-PK11195 is a selective ligand for translocator protein, 18kDa (TSPO), which is highly expressed on the surface of activated monocytes/macrophages. This part of the study was prematurely stopped due to problems with the production of the radiotracer with 11[C] (only 13 patients were studied with this approach).

Primary endpoints:

- The primary endpoint is to identify independent predictors (plaque-related or patient-related) with the progression of WMH through multivariable logistic regression analysis.

Progression of WMH was considered as dichotomous variable: progression versus no progression of WMH.

- The co-primary end-point is to identify independent predictors (plaque-related or patient-related) with the progression of gray matter (GM)/all brain atrophy through multivariable logistic regression analysis. Progression of brain atrophy was considered as dichotomous variable: progression versus no progression of GM/all brain atrophy.

Statistical considerations:

The investigators calculated the sample size for multivariate logistic regression analysis with a power of 0.8 and an alpha of 0.05. The investigators will analyze the highest tertile of carotid plaques burden in terms of plaque volume versus others (see Sillesen, 2012). By definition, the prevalence of high burden atherosclerosis will be 33%. The investigators estimated a clinically relevant probability of progressing in terms of WMH in the high burden group to be 50%, while subjects without high burden plaques are estimated to progress in terms of WMH as the general population with carotid atherosclerosis in a similar time frame. This probability would be estimated to be around 15% (see Dufoil, 2005 and Pico, 2002). The estimated sample size would be 58 individuals.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

- bearing an asymptomatic carotid stenosis of 30-70% in diameter, as established by Doppler-measured peak systolic flow velocity, according to the Society of Radiologists in Ultrasound Consensus Conference (Grant et al. Radiology 2003).

Exclusion Criteria:

  • pregnancy or possibility of pregnancy,
  • history of allergic diathesis,
  • history of stroke or transitory ischemic attack,
  • previous carotid artery stenting or carotid endarterectomy,
  • history of autoimmune vasculitis,
  • History of drug abuse, alcohol abuse or any psychiatric or social condition which may contraindicate the participation to a clinical study
  • life expectancy of less than 18 months due to underlying medical conditions,
  • presence of cognitive impairment preventing the patient from providing informed consent,
  • Atrial fibrillation or previous cardiac surgery or positioning of intracardiac devices (excluded coronary stents) as potential confounding causes of cerebral ischemic damage,
  • Known patent foramen ovale (PFO) necessitating anti-platelet treatment
  • Current anti-coagulation,
  • Previous infections to the central nervous system (CNS)
  • Previous surgery to the CNS
  • History of anoxic damage to the CNS
  • Dementia
  • Contraindications to computed tomography angiography (CTA, estimated Glomerular Filtration Rate<60 mL/min; history of allergic reaction to iodinated contrast media),
  • Specific contraindication to MRI:

    • Claustrophobia
    • Sickle cell anemia
    • Systemic mastocytosis
    • Implanted cardiac devices (i.e. pacemakers, implantable cardioverter defibrillators)
    • Vascular clips
    • Vertebral distractors
    • Infusion pumps
    • Neurostimulators
    • Liquor derivations
    • Any device which could be dispositioned in the presence of a strong magnetic field
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03333330


Sponsors and Collaborators
Enrico Ammirati
Investigators
Principal Investigator: Enrico Ammirati, Doctor ASST Grande Ospedale Metropolitano Niguarda and Università Vita-Salute San Raffaele; both in Milan, Italy
Study Chair: Paolo G Camici, Professor Università Vita-Salute San Raffaele and Hospital, Milan, Italy
  Study Documents (Full-Text)

Documents provided by Enrico Ammirati, Università Vita-Salute San Raffaele:
Study Protocol  [PDF] November 6, 2017
Statistical Analysis Plan  [PDF] November 6, 2017

  More Information

Publications:
Responsible Party: Enrico Ammirati, Principal Investigator of the grant number GR-2009-1608780 funded by the Italian Ministry of Health Grant, Università Vita-Salute San Raffaele
ClinicalTrials.gov Identifier: NCT03333330     History of Changes
Other Study ID Numbers: GR-2009-1608780
First Submitted: October 30, 2017
First Posted: November 6, 2017
Last Update Posted: November 8, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Enrico Ammirati, Università Vita-Salute San Raffaele:
Carotid atherosclerosis
Carotid plaque
Brain magnetic resonance imaging
Contrast enhanced ultrasound
Carotid CT angiography
Silent brain ischemia
Vascular cognitive impairment

Additional relevant MeSH terms:
Atherosclerosis
Carotid Artery Diseases
Carotid Stenosis
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Cardiovascular Diseases
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases