PET Imaging of Inflammation and Lipid Lowering Study (PIILL)

University of Cambridge

Status: Enrolling

Conditions: Carotid Artery Plaque; Hypercholesterolemia; Hypercholesterolemia, Familial; Atherosclerosis

Treatments: Diagnostic Test: 68Ga-DOTATATE PET-MRI; Drug: Colchicine; Drug: Inclisiran

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT04073797

A095007 (PIILL)

Details and patient eligibility

About

While 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging has been used as an early marker of drug efficacy in numerous clinical cardiovascular drug trials, as a glucose analog, its signal in the vasculature lacks inflammatory cell-specificity. Moreover, high background 18F-FDG signals from the myocardium often preclude coronary artery imaging, despite attempts to suppress myocardial tracer uptake by dietary manipulation. These limitations of 18F-FDG for measuring changes in vascular inflammation arising from drug intervention highlight important unmet needs, which might be overcome by using a somatostatin receptor subtype-2 (SST2) PET tracer.

Full description

Up-regulation of SST2 in activated macrophages represents a novel imaging target for measuring vascular inflammation, which has been previously examined in atherosclerosis using 68Ga-DOTATATE. To test the hypothesis that 68Ga-DOTATATE can quantify drug-induced changes in arterial inflammation, patients with primary hypercholesterolaemia (non-familial or familial) or mixed dyslipidaemia with stable cardiovascular Disease (CVD) and elevated LDL cholesterol ≥2.6 despite maximum tolerated statins with or without other lipid lowering therapies will undergo carotid artery 68Ga-DOTATATE PET-magnetic resonance imaging (MRI) in a randomised, double-blind, placebo-controlled study of inclisiran or colchicine.

In parallel, we will examine a novel method for detecting plaque composition based on analysis of ultrasound centre frequency shifts, which was developed by collaborators in Lund University, Sweden. The Ultrasound Plaque Structure Analysis (UPSA) method uses radiofrequency algorithms to create real-time tissue-like maps of carotid plaques. Participants in the study will undergo carotid ultrasound imaging using the UPSA method in addition to PET/MRI.

Enrollment: 63 estimated patients

Sex: All

Ages: 18 to 99 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Male or female participants >18 years old
• Able to give written, informed consent and to lie flat
• Have primary hypercholesterolaemia (non-familial or definite or possible heterozygous familial hypercholesterolaemia (HeFH) based on clinical criteria) or mixed dyslipidaemia, and
• History of CVD (acute coronary syndrome, coronary or other revascularisation procedures, coronary heart disease, ischaemic stroke, or peripheral arterial disease) and elevated LDL cholesterol ≥2.6 despite maximum tolerated statins with or without other lipid lowering therapies (see NICE TA 733), and
• Lipid lowering therapy unchanged for at least 6 weeks prior to screening, and
• Pre-existing carotid atherosclerotic plaque ≥15mm by B-mode ultrasound

Exclusion criteria

• Women of childbearing potential not using adequate contraception
• Contra-indication to MRI scanning
• Statin-associated myositis or liver function abnormality
• Already taking inclisiran or colchicine
• Sensitivity and/or contraindication to inclisiran or colchicine. Contraindications to colchicine include severe hepatic or renal impairment, blood disorders, and patients with renal or hepatic impairment who are taking a P-gp inhibitor or a strong CYP3A4 inhibitor
• Contrast allergy or contrast-nephropathy
• Chronic kidney disease (eGFR <30 mL/min/1.73 m2)
• Cardiovascular event within 6 months
• Any medical condition, in the opinion of the investigator, that prevents the participant from lying flat during scanning, or from participating in the study
• Uncontrolled chronic inflammatory disorder
• History of recent malignancy deemed relevant to the study by the investigator
• Treatment with medications that result in significant drug to drug interactions with the study medications
• Current use of systemic corticosteroids or other immunosuppressive drugs
• Previous or planned carotid endarterectomy surgery or stenting on the index side

Trial design

Primary purpose: Diagnostic

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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63 participants in 3 patient groups, including a placebo group

Stable CVD - treatment

Experimental group

Description:

Stable CVD with LDL ≥2.6 despite maximally tolerated statins ± other lipid lowering therapies, randomised to add on therapy with inclisiran + placebo tablet

Treatment:

Drug: Inclisiran

Diagnostic Test: 68Ga-DOTATATE PET-MRI

Stable CVD - placebo control

Active Comparator group

Description:

Stable CVD with LDL ≥2.6 despite maximally tolerated statins ± other lipid lowering therapies, randomised to placebo injection + colchicine tablet

Treatment:

Drug: Colchicine

Diagnostic Test: 68Ga-DOTATATE PET-MRI

HeFH - treatment

Placebo Comparator group

Description:

Stable CVD with LDL ≥2.6 despite maximally tolerated statins ± other lipid lowering therapies, randomised to placebo injection + placebo tablet

Treatment:

Drug: Inclisiran

Diagnostic Test: 68Ga-DOTATATE PET-MRI