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AzTrials

Carotid Artery PlaquePhase 3IMPLACNCT03333330

IMaging Della PLAcca Carotidea

A Phase 3 study testing Visipaque 320 and SonoVue in people with Carotid Artery Plaque and Atherosclerosis, run by Enrico Ammirati.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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… Read more about this study

Who is it for?
Ages 18 to 85 years
What is being tested?
Visipaque 320 and SonoVue
Could I receive a placebo?
No, everyone receives an active treatment
How many people
75 participants
Where
No sites listed yet
Study dates
Apr 2012to Oct 2017
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 85 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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).

Who cannot join

  • 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
Show all 27Show fewer
  • 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

About this study

Official title: Non Invasive Vascular Imaging Combined With Systemic Biomarkers and Brain Magnetic Resonance Imaging for Identification of Asymptomatic Patients With Unstable Carotid Atherosclerosis

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%.

Read the 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.

Being tested
Visipaque 320 and SonoVue
Keywords
Carotid atherosclerosis, Carotid plaque, Brain magnetic resonance imaging, Contrast enhanced ultrasound, Carotid CT angiography, Silent brain ischemia, Vascular cognitive impairment
Medical subject headings
Carotid Stenosis, Atherosclerosis, Ischemic Stroke, Carotid Artery Diseases

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Visipaque 320 and SonoVueDrug

    Also called Contrast agents

    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

Study groups in NCT03333330
Study groupRoleWhat they receive
Carotid imaging with Visipaque 320 and SonoVueExperimentalPatients 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
Receives: Drug: Visipaque 320 and SonoVue

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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)

    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.

    Measured: 18 months

Secondary outcomes (4)

  1. Changes of total brain volume and grey matter volume from baseline

    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.

    Measured: 18 months

  2. 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)

    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.

    Measured: 18 months

  3. Changes of the carotid total plaque area and extent of CEUS positive plaques

    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.

    Measured: 18 months

  4. 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

    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.

    Measured: at baseline

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Nov 2017
  2. Study startApr 2012
  3. Primary completionOct 2017
  4. Study completionOct 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Diagnosis
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
75 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03333330
Sponsor's protocol ID
GR-2009-1608780
Acronym
IMPLAC
Status last verified
Feb 2018
First submitted
30 Oct 2017
Last updated
19 Feb 2018
Results posted
No
Data monitoring committee
Yes
Individual data sharing
Undecided

Publications

  • Ammirati E, Moroni F, Magnoni M, Rocca MA, Messina R, Anzalone N, De Filippis C, Scotti I, Besana F, Spagnolo P, Rimoldi OE, Chiesa R, Falini A, Filippi M, Camici PG. Relation between characteristics of carotid atherosclerotic plaques and brain white matter hyperintensities in asymptomatic patients. Sci Rep. 2017 Sep 5;7(1):10559. doi: 10.1038/s41598-017-11216-x.

    PubMed 28874779

  • Ammirati E, Moroni F, Magnoni M, Di Terlizzi S, Villa C, Sizzano F, Palini A, Garlaschelli K, Tripiciano F, Scotti I, Catapano AL, Manfredi AA, Norata GD, Camici PG. Circulating CD14+ and CD14highCD16- classical monocytes are reduced in patients with signs of plaque neovascularization in the carotid artery. Atherosclerosis. 2016 Dec;255:171-178. doi: 10.1016/j.atherosclerosis.2016.10.004. Epub 2016 Oct 6.

    PubMed 27751505

  • Ammirati E, Magnoni M, Moroni F, Di Terlizzi S, Scotti I, Villa C, Sizzano F, Impellizzeri M, Fanelli G, Esposito G, Chiesa R, Camici PG. Reduction of Circulating HLA-DR+ T Cell Levels Correlates With Increased Carotid Intraplaque Neovascularization and Atherosclerotic Burden. JACC Cardiovasc Imaging. 2016 Oct;9(10):1231-1233. doi: 10.1016/j.jcmg.2015.10.010. Epub 2016 Jan 6. No abstract available.

    PubMed 26777226

  • Moroni F, Magnoni M, Vergani V, Ammirati E, Camici PG. Fractal analysis of plaque border, a novel method for the quantification of atherosclerotic plaque contour irregularity, is associated with pro-atherogenic plasma lipid profile in subjects with non-obstructive carotid stenoses. PLoS One. 2018 Feb 12;13(2):e0192600. doi: 10.1371/journal.pone.0192600. eCollection 2018.

    PubMed 29432486

  • Ammirati E, Moroni F, Magnoni M, Rocca MA, Anzalone N, Cacciaguerra L, Di Terlizzi S, Villa C, Sizzano F, Palini A, Scotti I, Besana F, Spagnolo P, Rimoldi OE, Chiesa R, Falini A, Filippi M, Camici PG. Progression of brain white matter hyperintensities in asymptomatic patients with carotid atherosclerotic plaques and no indication for revascularization. Atherosclerosis. 2019 Aug;287:171-178. doi: 10.1016/j.atherosclerosis.2019.04.230. Epub 2019 May 6.

    PubMed 31101367

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Visipaque 320 and SonoVue in people with Carotid Artery Plaque and Atherosclerosis, run by Enrico Ammirati.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 1 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Feb 2018. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03333330, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Feb 2018.

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