CARotid Mri of Atherosclerosis (CARMA)

December 7, 2022 updated by: Ebo De Muinck, Linkoeping University

In the entire world most people die from cardiovascular disease. Death is primarily from myocardial infarction (MI) and stroke which are most often caused by rupture of atherosclerotic plaques. Patients with high-grade, i.e. ≥ 70% carotid artery stenosis are at especially high risk. Magnetic Resonance Imaging (MRI) studies show that two features inside plaques that are associated with the risk of plaque rupture and subsequent cardiovascular events are: lipid rich necrotic core (LRNC) and intraplaque hemorrhage (IPH).

MRI studies on carotid artery plaques typically relies on proton-density-weighted fast-spin echo, blood-suppressed T1- and T2-weighted gradient-echo sequences. The end-result is nonquantitative measures, where plaque features are identified due to their relative signal intensity. To address these problems of non-specificity, we developed a quantitative MRI (qMRI) technique based on Dixon sequences.

The study intention is to enable in-depth analysis of plaque features and their relation to clinical data. For example there is an insufficient understanding of associations between lipid biomarkers and plaque contents. Our hypothesis is that we can identify quantitative changes in both plaque and lipid biomarkers after one year of optimized cardiovascular risk management (including treatment with lipid lowering drugs), and establish if there is any associations between these features. Because there is a well-established link between systemic inflammation and the presence of atherosclerotic plaques we will also study the relationship between LRNC and IPH as measured by qMRI versus circulating markers of inflammation.

Method: Patients with known carotid stenosis are invited for a baseline visit and a 1-year follow up visit. The study visits include clinical assessment, blood tests, patient interview and magnetic resonance imaging of the carotid arteries. All participants are offered optimized cardiovascular risk management through the individual assessment by the study physicians.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Regarding quality assurance plans that address data validation and registry procedures, the current study is a single centre investigator-initiated study and therefore there are no plans for site monitoring and auditing. The reliability and validity of the MRI data has been previously confirmed with comparison to 3D histology data (Koppal et al. Quantitative fat and R2* mapping in vivo to measure lipid-rich necrotic core and intraplaque hemorrhage in carotid atherosclerosis. Magn Reson Med. 2017;78(1):285-96.).

Concerning data checks, intraobserver reliability regarding baseline and follow-up measurements will be ascertained (Intraclass Correlation Coefficients (ICC), Bland Altman).

Data is collected from patient medical records (electronic), dedicated study record forms (paper) and clinical assessments, resulting in quantitative measures. These external data sources are transferred into a study database.

The current study is a clinical study, using only clinically validated laboratory parameters. The source of the lab values and their normal ranges is the electronic patient record. The normal ranges have been established by the clinical chemistry and haematology laboratories at Linköping University Hospital. Clinical diagnosis and procedures are recorded using the International Classification of Diseases (ICD) classification.

The study was approved by the Swedish Ethical Review Authority (approval nr: 2016-441-31) and performed in accordance with the Declaration of Helsinki. Written informed consent has been obtained from all study participants.

Patients are selected based on duplex ultrasound criteria established for the European Carotid Surgery Trial. A cut-off at doppler flow velocity has been used to identify eligible patients and after considering inclusion and exclusion criteria patients have been contacted by the study clinicians dr Elin Good or dr Ebo de Muinck for recruitment. Any registration for adverse events follows the same procedures as in routine care.

Sample size assessment was based on results from previous studies in relation to our primary outcome variables. For example, one study with 24 patients and a follow-up time of three months experienced a significant reduction of lipid rich necrotic core, using magnetic resonance imaging (Alkhalil et al. T2 mapping MRI technique quantifies carotid plaque lipid, and its depletion after statin initiation, following acute myocardial infarction. Atherosclerosis. 2018;279:100-6.). Therefore, we aimed to include 50 patients who have completed both baseline and follow-up, and the follow-up time was set to 12 months.

Our plan for missing data in situations where variables are missing, unavailable, non-reported, uninterpretable etc is to not exclude the study participant, in order to avoid bias. For example, in cases where the imaging data from one patient is lost, we will still use the remaining clinical data from that patient if the patient has been included in the study.

Regarding Statistical analysis, SPSS Statistics 26 (International Business Machines Corporation, New York, NY, USA) is used for statistical analysis. Continuous variables are summarized as mean ± standard deviation (SD). To address the primary objectives (the strength of the association between fat fraction (FF) and R2*) Pearson correlation coefficient is used, and Paired-samples T test is used for analysing changes in quantitative values between baseline and follow-up.

Intra-observer repeatability measurements were calculated using ICC. For ICC evaluation we used two-way random effect models, checking for absolute agreement, average measures presented.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
52

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

- Carotid plaques with a cut-off at doppler flow velocity ≥ 1.3 m/sec at a Doppler angle of 50-60°, which corresponds to a ≥ 50% stenosis according to these criteria.

Exclusion Criteria:

  • Performed or planned carotid surgery
  • Carotid occlusion
  • Renal failure (GFR <45 ml/h)
  • Inflammatory diseases, anti-inflammatory treatment or malignancies
  • Stroke <30 days before admission
  • Co-morbidities that disable informed consent or participation in the study investigations (e.g. contraindications for MRI)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: CARMA study participants
All patients in the study are in the same treatment arm: all were treated for 12 months according to routine care and international guidelines for cardiovascular disease prevention in patients with very high cardiovascular risk. Through study physicians patients received an individual assessment and optimized cardiovascular risk management, including life style advice and adjustments in their medical preventive treatment, based on drugs used in standard care (eg. lipid lowering medication, anti-hypertensive-treatment, anti-thrombotic treatment). All treatment goals were set in accordance with current guidelines at the time for study participation.
Other: Optimization of cardiovascular risk management

Treatment goals were set according to current guidelines (Perk et al. Eur Guidelines on CVD prevention in clinical practice (2012). Eur heart J. 2012;33(13):1635-701):

  • blood pressure <140/90 mmHg
  • Tot cholesterol <5 mmol/l
  • LDL <1,8 mmol/l
  • Waist circumference: men <94 cm, women <80 cm
  • BMI <25 kg/m2
  • HbA1c without diabetes mellitus <42 mmol/mol, HbA1c with diabetes mellitus <52 mmol/mol
  • Antithrombotic treatment (or anticoagulants, if indicated)
  • Physical activity 30 min/day, 5 days/week, alternatively high-intensity training at least15 min/day, 5 days/week or a combination of the two.
  • Healthy diet, including low levels of saturated fats, high intake of vegetables, fruits, whole-grain and fish
  • Smoking cessation
  • Low alcohol consumption

Patients were encouraged to follow the above recommendations through support of the study physicians, who made individual assessments of all patients and adjusted ongoing medical treatment to reach treatment targets.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Changes in fat fraction (FF) and R2* in relation to changes in plasma lipoproteins.
Time Frame: Baseline - 1-year follow up
FF, Fat Fraction. Measured by Dixon MRI sequences, quantitatively corresponding to lipid rich necrotic core. R2* (= 1/T2*) is the rate of signal loss, it can be viewed as a measure for the presence of (heme) iron. As we have shown in a previous study, it correlates to the extent of intraplaque hemorrhage.
Baseline - 1-year follow up

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Changes in fat fraction (FF) and R2* in relation to changes in inflammatory lymphocyte subtypes
Time Frame: Baseline - 1-year follow up
For FF and R2*, see above. Inflammatory lymphocytes subtypes are measured using flow cytometry, with focus on lymphocyte T cell subtypes and Natural Killer cells.
Baseline - 1-year follow up

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Linkoeping University

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Region Östergötland
Region Jönköping County
FORSS, Forskningsrådet i Sydöstra Sverige

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Ebo de Muinck, Professor, Linkoeping University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 6, 2017

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 12, 2018

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 31, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
April 5, 2021

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 5, 2021

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 8, 2021

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
December 8, 2022

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 7, 2022

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 756191

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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