Carotid StenosisCARMANCT04835571
CARotid Mri of Atherosclerosis
A study testing Optimization of cardiovascular risk management in people with Carotid Stenosis and Carotid Artery Plaque, run by Linkoeping University.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Carotid Stenosis, Carotid Artery Plaque, Carotid Atherosclerosis
- What is being tested?
- Optimization of cardiovascular risk management
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 52 participants
- Where
- No sites listed yet
- Study dates
- 6 Jan 2017to 31 Dec 2021
- Phase
- Interventional
- 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 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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)
About this study
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.
Read more
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.
Read the 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.
- Being tested
- Optimization of cardiovascular risk management
- Keywords
- Carotid stenosis, Cardiovascular MRI, Atherosclerotic plaque
- Medical subject headings
- Carotid Stenosis, Carotid Artery Diseases, Plaque, Atherosclerotic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Optimization of cardiovascular risk managementOther
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.
| Study group | Role | What they receive |
|---|---|---|
| CARMA study participants | Experimental | 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. Receives: Other: Optimization of cardiovascular risk management |
What is being measured
The primary outcome is the main question the study is designed to answer.
Changes in fat fraction (FF) and R2* in relation to changes in plasma lipoproteins.
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.
Measured: Baseline - 1-year follow up
Secondary outcomes (1)
Changes in fat fraction (FF) and R2* in relation to changes in inflammatory lymphocyte subtypes
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.
Measured: Baseline - 1-year follow up
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Apr 2021
- Study start6 Jan 2017
- Primary completion12 Dec 2018
- Study completion31 Dec 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Carotid StenosisStudies of the same condition, open and under way.
- More trials run by Linkoeping UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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 N/A
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Single group, repeated measures design. The treatment is
- Masking
- None (open label)
- Enrolment
- 52 participants (actual)
Sponsor and investigators
- Lead sponsor
- Linkoeping University
- Sponsor type
- Other government
- Collaborators
- Region Östergötland, Region Jönköping County, FORSS, Forskningsrådet i Sydöstra Sverige
- Responsible party
- Principal investigator, Ebo De Muinck, Linkoeping University
- Investigators
- Ebo de Muinck, Professor, Principal investigator, Linkoeping University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04835571
- Sponsor's protocol ID
- 756191
- Acronym
- CARMA
- Status last verified
- Dec 2022
- First submitted
- 5 Apr 2021
- Last updated
- 8 Dec 2022
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
Koppal S, Warntjes M, Swann J, Dyverfeldt P, Kihlberg J, Moreno R, Magee D, Roberts N, Zachrisson H, Forssell C, Lanne T, Treanor D, de Muinck ED. Quantitative fat and R2* mapping in vivo to measure lipid-rich necrotic core and intraplaque hemorrhage in carotid atherosclerosis. Magn Reson Med. 2017 Jul;78(1):285-296. doi: 10.1002/mrm.26359. Epub 2016 Aug 11.
PubMed 27510300Good E, Lanne T, Wilhelm E, Perk J, Jaarsma T, de Muinck E. High-grade carotid artery stenosis: A forgotten area in cardiovascular risk management. Eur J Prev Cardiol. 2016 Sep;23(13):1453-60. doi: 10.1177/2047487316632629. Epub 2016 Feb 15.
PubMed 26879568Good E, Akerman L, Nystrom S, Jonasson L, Ernerudh J, de Muinck E. Changes in natural killer and T lymphocyte phenotypes in response to cardiovascular risk management. Sci Rep. 2023 Nov 27;13(1):20810. doi: 10.1038/s41598-023-48111-7.
PubMed 38012327
Study at a glance
From the registry record, last updated by the sponsor on 8 Dec 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- CARotid Mri of Atherosclerosis
- ClinicalTrials.gov ID
- NCT04835571
- Acronym / sponsor ID
- CARMA / 756191
- Keywords
- Carotid stenosis, Cardiovascular MRI, Atherosclerotic plaque
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 52 participants (actual)
- Lead sponsor
- Linkoeping UniversityOther government
- Collaborators
- Region Östergötland, Region Jönköping County, FORSS, Forskningsrådet i Sydöstra Sverige
- Study start
- 6 Jan 2017 (actual)
- Primary completion
- 12 Dec 2018 (actual)
- Study completion
- 31 Dec 2021 (actual)
- First posted
- 8 Apr 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Single group, repeated measures design. The treatment is
| Arm | Type | Receives |
|---|---|---|
| CARMA study participants | Experimental | Other: Optimization of cardiovascular risk managementAll 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. |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- 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.
Key exclusion criteria (6 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Optimization of cardiovascular risk managementTreatment 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. | Other | CARMA study participants |
Primary outcome
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.
1 secondary outcome
Changes in fat fraction (FF) and R2* in relation to changes in inflammatory lymphocyte subtypes
Time frame: Baseline - 1-year follow up
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Dec 2022.
- Background: PubMed 27510300Koppal S, Warntjes M, Swann J, Dyverfeldt P, Kihlberg J, Moreno R, Magee D, Roberts N, Zachrisson H, Forssell C, Lanne T, Treanor D, de Muinck ED. Quantitative fat and R2* mapping in vivo to measure lipid-rich necrotic core and intraplaque hemorrhage in carotid atherosclerosis. Magn Reson Med. 2017 Jul;78(1):285-296. doi: 10.1002/mrm.26359. Epub 2016 Aug 11.
- Background: PubMed 26879568Good E, Lanne T, Wilhelm E, Perk J, Jaarsma T, de Muinck E. High-grade carotid artery stenosis: A forgotten area in cardiovascular risk management. Eur J Prev Cardiol. 2016 Sep;23(13):1453-60. doi: 10.1177/2047487316632629. Epub 2016 Feb 15.
- Derived from this study: PubMed 38012327Good E, Akerman L, Nystrom S, Jonasson L, Ernerudh J, de Muinck E. Changes in natural killer and T lymphocyte phenotypes in response to cardiovascular risk management. Sci Rep. 2023 Nov 27;13(1):20810. doi: 10.1038/s41598-023-48111-7.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ebo de Muinck, Professor principal investigator
Linkoeping University
Questions about this trial
What is this clinical trial studying?
A study testing Optimization of cardiovascular risk management in people with Carotid Stenosis and Carotid Artery Plaque, run by Linkoeping University.
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 6 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 8 Dec 2022. 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.
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 in fat fraction (FF) and R2* in relation to changes in plasma lipoproteins. (time frame: Baseline - 1-year follow up). 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 NCT04835571, which also lists 3 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 8 Dec 2022.