This observational, multicenter, retrospective and prospective study aims to evaluate the impact of intensified lipid-lowering therapy including Evinacumab on coronary atherosclerotic plaque burden in patients with Homozygous Familial Hypercholesterolemia (HoFH).
HoFH is a rare genetic disorder characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C) levels from early life and a markedly increased risk of premature atherosclerotic cardiovascular disease. Despite combination lipid-lowering therapy, many patients do not achieve recommended LDL-C targets and remain at high cardiovascular risk.
Evinacumab, a monoclonal antibody targeting angiopoietin-like protein 3 (ANGPTL3), has demonstrated significant LDL-C reduction in clinical trials. However, real-world evidence on its impact on coronary plaque progression is limited.
The study will compare HoFH patients receiving intensified lipid-lowering therapy including Evinacumab with patients receiving conventional lipid-lowering therapy without Evinacumab. Coronary plaque burden and phenotype will be assessed using coronary computed tomography angiography (CCTA) performed as part of routine clinical practice.
Approximately 52 patients will be enrolled across European centers. The primary objective is to evaluate changes in non-calcified coronary plaque volume between baseline and 18-24 months' follow-up. Secondary objectives include evaluation of total plaque burden, high-risk plaque characteristics, and LDL-C reduction. Exploratory analyses will assess patient-reported outcomes, pericoronary adipose tissue characteristics, and supravalvular atherosclerosis.
All data are collected from routine clinical care. No additional procedures are mandated by the protocol. This study aims to generate real-world imaging evidence on the effect of intensified lipid-lowering therapy including Evinacumab on coronary atherosclerosis in HoFH.
Willing and able to provide written informed consent form/assent form for the use of retrospective and prospective data.
Male or female patients aged ≥12 years old at time of enrolment (exception for Italy and France ≥18 years).
Clinical or genetic diagnosis of Homozygous Familial Hypercholesterolemia (HoFH) according to the consensus statement by Cuchel et al, 2023; EHJ (14).
Patients who initiated Evinacumab (at the approved dosage and administration) within 24 months before enrolment as add-on to lipid-lowering treatment (with statins, ezetimibe, PCSK9i and/or other agents or treatment) at stable dose for at least 30 days before Evinacumab initiation, as per routine clinical care and no change in dosing is anticipated.
Patients participating in a clinical trial with an investigational drug within the last 6 months.
Patients treated outside of Evinacumab approved indication.
Inability to access adequate retrospective clinical data from medical records.
Inability or unwillingness to provide informed consent/assent or refusal to participate.
Intensified treatment group: Male and Female HoFH patients aged ≥12 (exception for Italy and France ≥18 years) who initiated commercially available Evinacumab (at the approved dosage and administration) as add-on lipid-lowering treatment at stable dose for at least 30 days before Evinacumab initiation, in the routine clinical care. Conventional treatment group: Male and Female HoFH patients aged ≥12 (exception for Italy and France ≥18 years) on standard lipid-lowering therapy at stable dose for at least 30 days before the baseline CCTA from: 1. countries where Evinacumab will not be commercially available within the next 18 months; 2. participating countries who have the explicit wish not to receive treatment with Evinacumab.
Cohort
Other
Not listed
Stabilization or regression of atherosclerotic coronary plaques as measured by CCTA in Evinacumab patients vs conventional ones
This measure will compare the change in percent of non-calcified coronary plaque volume (NCPV) between baseline and follow-up, as assessed by CCTA, in HoFH patients receiving intensified lipid lowering therapy including Evinacumab versus those managed with conventional lipid-lowering therapy under routine clinical care.
Change in absolute NCPV, TPV and CPV
Asses changes in absolute NCPV, total plaque volume (TPV) and calcified plaque volume (CPV) from baseline to follow-up within each treatment group.
Change in percent NCPV, PAV and CPV
Asses changes in percent NCPV, percent atheroma volume (PAV) and percent CPV from baseline to follow-up within each treatment group.
Change in absolute and percent NCPV, TPV, CPV and PAV
Assess Differences in change between groups (Evinacumab vs. conventional therapy) for absolute and percent NCPV, TPV, CPV, and PAV.
Low attenuation non-calcified plaque volume
Assess low attenuation non-calcified plaque volume (ideally \<30 HU)
Changes in patient reported outcomes (SAQ-7)
Assess symptoms related to angina pectoris using a standard questionnaire (SAQ-7) from baseline to follow-up in the intensified treatment and conventional treatment comparator group and also between the two groups. The Seattle Angina Questionnaire is used to assess the frequency and impact of chest pain, chest tightness, or angina over the previous four weeks. The questionnaire evaluates physical limitation during daily activities, frequency of angina episodes, frequency of nitroglycerin use, the extent to which symptoms limit enjoyment of life, and overall satisfaction with current symptom status. Responses are provided using Likert-type scales, with higher scores reflecting better health status and fewer symptom-related limitations.
Change in PCAT attenuation in RCA
Assess changes in PCAT Attenuation (Hounsfield Units) in Right Coronary Artery (RCA).
Characterization of supravalvular atherosclerosis
Characterization of supravalvular atherosclerosis as assessed by available CCTA, including its presence, distribution, and potential changes over time.
Changes in patient reported outcomes (Rose Dyspnea Scale)
Assess symptoms related to dyspnea using a standard questionnaire (Rose Dyspnea Scale) from baseline to follow-up in the intensified treatment and conventional treatment comparator group and also between the two groups. The Dyspnea Score ranges from 0 to 4: a score of 0 indicates no dyspnea; 1 indicates dyspnea only when hurrying or walking up a hill; 2 indicates dyspnea when walking on level ground with people of the same age; 3 indicates dyspnea when walking at one's own pace on level ground; 4 indicates dyspnea during activities of daily living such as washing or dressing.
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Fondazione SISA (Societa Italiana per lo Studio della Arteriosclerosi)
Lead sponsor
Ultragenyx Pharmaceutical Inc
Collaborator
CMV-Stat S.r.l.
Collaborator
Clinical Trial Consulting s.s.
Collaborator
