18F-Flutemetamol and Plaque Vulnerability

Identification of Plaque Vulnerability Wit PET/MRI: a Feasibility Study of 18F-Flutemetamol in Atherosclerosis

Rationale: Amyloid beta (Ab) is mainly known for its role in Alzheimer's disease (AD) pathology. However, Ab seems not only to be involved in AD pathology, but also in atherosclerosis, which might explain the remarkable similarities in risk factors between these two pathologies. In vitro studies suggest that a major part of this association is based on the ability of amyloid to lead to macrophage activation and thus inflammation. These data lead to the hypothesis that Ab is associated with plaque vulnerability.

18F-Flutemetamol is a PET tracer with high affinity for Ab. This has been extensively studied in AD patients.

Objective: To validate 18F-Flutemetamol PET in the evaluation of plaque vulnerability.

Study design: A cross-sectional validation study. Study population: 25 adults, who have recently (<14days) experienced a transient ischemic attack (TIA) or stroke with a carotid artery plaque of ≥30% and without evidence of another etiology than carotid atherosclerosis (i.e. cardiac or small vessel).

Of these 25 patients, 10 patients will be included who have been scheduled for carotid endarterectomy (CEA). The other 15 will be selected of patients who are not scheduled to undergo CEA.

Intervention: All patients will undergo a PET/MRI scan with 18F-Flutemetamol, either before the scheduled CEA or within the first 30 days following the cerebrovascular event. Imaging will include the carotid and coronary arteries as well as the brain.

Main study parameters/endpoints: Tracer uptake in the carotid artery will be correlated to vulnerable plaque characteristics as assessed by MRI. In the 10 CEA patients, tracer uptake and MR imaging of different plaque characteristics will be validated with plaque histology of the surgically removed specimen.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: There is no additional benefit for study subjects. Study subjects will receive the same treatment as non-participating patients. Patients will be screened for in- and exclusion criteria to minimize risks.

For optimal MR imaging patients will be injected with a Gadolinium based contrast agent, which is a common procedure and associated with very low risk of complications. The PET tracer 18F-flutemetamol has been studied extensively and is currently used in patients with AD. Adverse events were not frequent and mainly mild. The radioactivity dose will be around 6.8 mSv.

Study Overview

• Status: Unknown
• Conditions: Atherosclerosis
• Intervention / Treatment: Drug: 18F-Flutemetamol PET/MRI

• Study Type: Interventional
• Enrollment (Anticipated): 25
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Limburg
    • Maastricht, Limburg, Netherlands, 6229 HX
      • Recruiting
      • Maastricht University Medical Centre (MUMC+)
      • Contact: Ellen Boswijk, MD; Phone Number: +31433876549; Email: ellen.boswijk@mumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

In order to be eligible to participate in this study, a subject must meet all of the following criteria:

• All patients:

  • Age18years and older (no maximum age)
  • Informed consent by signed informed consent form regarding this study

• Patients, who are scheduled for carotid endarterectomy:

  o Inclusion criteria for carotid endarterectomy:

  • Symptomatic stenosis (TIA or CVA) within last 14days and high grade stenosis (70-99%)
  • In men, carotid artery stenosis between 50-69% is considered significant when related to clinical symptoms

• Patients, who are not scheduled for carotid endarterectomy:

  • Patients who have experienced a TIA/CVA/amaurosis fugax (a 'TIA of the eye') within the last 14 days and abnormal findings on imaging of the carotids:

    • Women with an ipsilateral carotid artery stenosis between 30-69% based on duplex ultrasonography, CTA, or MRA
    • Men with an ipsilateral carotid artery stenosis between 30-49% based on duplex ultrasonography, CTA, or MRA
    • Patients meeting inclusion criteria for carotid endarterectomy, but with contra- indications for CEA

Exclusion Criteria:

• All patients:

  • Severe cognitive impairment, neurological deficit or comorbidity causing the study to be too high a burden for the patient or disrupting patient's co- operation with scan procedures
  • Evident other causality for stroke (cardiac embolus, small vessel disease or thrombogenic diathesis)
  • Pregnant women and nursing mothers

  • Contra-indications for MRI (49):

    • Ferromagnetic implants, such as pacemakers and other electronic implants
    • Ferromagnetic (intracerebral) vascular clips
    • Metallic cochlear implants
    • Metallic splinters in eye(s) or other magnetic metallic foreign bodies elsewhere
    • Claustrophobia

  • Relative contra-indications for MRI-contrast agents (50):

    • GFR <30ml/min/1,73m2
    • Previous allergic reaction to MRI contrast agent

  • Contra-indication 18F-Flutemetamol:

    • Known allergic reaction to flutemetamol or polysorbate 80 or any of the excipients.
    • Severe liver dysfunction.

• Patients undergoing CEA:

  • Comorbidity associated with high operative risk
  • Occlusion of the internal carotid artery on the symptomatic side
  • Near occlusion on the symptomatic side
  • Complete infarction of the symptomatic anterior circulation/severe neurological deficit

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 18F-Flutemetamol PET/MRI dynamic; All included patients will be patients with a recent stroke and a significant carotid plaque. The first 5 patients will undergo a slightly longer scan protocol to determine optimal scan time for the use of 18F-Flutemetamol in atherosclerosis imaging.	Drug: 18F-Flutemetamol PET/MRI; All patients will undergo a PET/MRI of the carotids after 18F-Flutemetamol injection.
Experimental: 18F-Flutemetamol PET/MRI CEA; 10 patients will be selected from patients that will undergo carotid endarterectomy (CEA) and will undergo the the optimized (shorter) scan protocol with 18F-Flutemetamol. The decision for this operation is made by the surgeon and neurologist and based on clinical standards and is thus independent of study participation.	Drug: 18F-Flutemetamol PET/MRI; All patients will undergo a PET/MRI of the carotids after 18F-Flutemetamol injection.
Experimental: 18F-Flutemetamol PET/MRI; The remaining 10 patients will undergo the optimized (shorter) scan protocol with 18F-Flutemetamol.	Drug: 18F-Flutemetamol PET/MRI; All patients will undergo a PET/MRI of the carotids after 18F-Flutemetamol injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
18F-Flutemetamol uptake carotids	measured as SUV and TBR	0-120min

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
18F-Flutemetamol uptake coronaries	measured as SUV and TBR	0-150min
18F-Flutemetamol uptake in the brain	measured as SUVR	0-150min
CEA - plaque inflammation	macrophage content	1-14 dys
MRI plaque characteristics carotid	semi quantitive analysis	0-150min
CEA - plaque amyloid burden	Immunohistochemistry	1-14 dys

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2018
• Primary Completion (Anticipated): December 31, 2019
• Study Completion (Anticipated): December 31, 2019

Study Registration Dates

• First Submitted: September 19, 2017
• First Submitted That Met QC Criteria: September 19, 2017
• First Posted (Actual): September 25, 2017

Study Record Updates

• Last Update Posted (Actual): July 11, 2019
• Last Update Submitted That Met QC Criteria: July 10, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: PET/MRI; Amyloid; Flutemetamol
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Molecular Mechanisms of Pharmacological Action; Radiopharmaceuticals; Flutemetamol
• Other Study ID Numbers: NL58543.068.16

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No