PET Imaging of Inflammation and Lipid Lowering Study

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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PET Imaging of Inflammation and Lipid Lowering Study

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

Intervention / Treatment
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* Drug: Inclisiran
* Diagnostic Test: 68Ga-DOTATATE PET-MRI
* Drug: Colchicine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stable CVD - treatment<br>Stable CVD with LDL ≥2.6 despite maximally tolerated statins ± other lipid lowering therapies, randomised to add on therapy with inclisiran + placebo tablet | Drug: Inclisiran<br>* Inclisiran 284 mg, one injection<br>Diagnostic Test: 68Ga-DOTATATE PET-MRI<br>* 68Ga-DOTATATE PET-MRI at baseline and 12 weeks<br>|
| Active Comparator: Stable CVD - placebo control<br>Stable CVD with LDL ≥2.6 despite maximally tolerated statins ± other lipid lowering therapies, randomised to placebo injection + colchicine tablet | Diagnostic Test: 68Ga-DOTATATE PET-MRI<br>* 68Ga-DOTATATE PET-MRI at baseline and 12 weeks<br>Drug: Colchicine<br>* Colchicine 500 mcg tablet once daily<br>|
| Placebo Comparator: HeFH - treatment<br>Stable CVD with LDL ≥2.6 despite maximally tolerated statins ± other lipid lowering therapies, randomised to placebo injection + placebo tablet | Drug: Inclisiran<br>* Inclisiran 284 mg, one injection<br>Diagnostic Test: 68Ga-DOTATATE PET-MRI<br>* 68Ga-DOTATATE PET-MRI at baseline and 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Carotid 68Ga-DOTATATE PET | Relative change from baseline in carotid artery 68Ga-DOTATATE tissue-to-blood ratio in the index vessel | 12 weeks | 
| Carotid UPSA imaging | Relative change from baseline in carotid artery UPSA signal in the index vessel | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MRI plaque burden | Relative change from baseline in carotid artery total plaque burden and lipid-rich necrotic core measured by MRI | 12 weeks | 
| Carotid 68Ga-DOTATATE vs. serum lipids | Comparison of carotid 68Ga-DOTATATE imaging to serum lipids | 12 weeks | 
| Carotid 68Ga-DOTATATE vs. hsCRP | Comparison of carotid 68Ga-DOTATATE imaging to high-sensitivity C-reactive protein (hsCRP) | 12 weeks |