PET Imaging of Inflammation and Lipid Lowering Study (PIILL)

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.

Study Overview

• Status: Recruiting
• Conditions: Atherosclerosis; Carotid Artery Plaque; Hypercholesterolemia; Hypercholesterolemia, Familial
• Intervention / Treatment: Drug: Inclisiran; Diagnostic test: 68Ga-DOTATATE PET-MRI; Drug: Colchicine

Detailed 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.

• Study Type: Interventional
• Enrollment (Anticipated): 63
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridge, United Kingdom
    • Recruiting
    • University of Cambridge

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Cambridge
• Collaborators: Lund University; GE Healthcare; Cambridge University Hospitals NHS Foundation Trust; Wellcome Trust

Publications and helpful links

General Publications

• Tarkin JM, Joshi FR, Evans NR, Chowdhury MM, Figg NL, Shah AV, Starks LT, Martin-Garrido A, Manavaki R, Yu E, Kuc RE, Grassi L, Kreuzhuber R, Kostadima MA, Frontini M, Kirkpatrick PJ, Coughlin PA, Gopalan D, Fryer TD, Buscombe JR, Groves AM, Ouwehand WH, Bennett MR, Warburton EA, Davenport AP, Rudd JH. Detection of Atherosclerotic Inflammation by 68Ga-DOTATATE PET Compared to [18F]FDG PET Imaging. J Am Coll Cardiol. 2017 Apr 11;69(14):1774-1791. doi: 10.1016/j.jacc.2017.01.060.
• Pedersen SF, Sandholt BV, Keller SH, Hansen AE, Clemmensen AE, Sillesen H, Hojgaard L, Ripa RS, Kjaer A. 64Cu-DOTATATE PET/MRI for Detection of Activated Macrophages in Carotid Atherosclerotic Plaques: Studies in Patients Undergoing Endarterectomy. Arterioscler Thromb Vasc Biol. 2015 Jul;35(7):1696-703. doi: 10.1161/ATVBAHA.114.305067. Epub 2015 May 14.

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2023
• Primary Completion (Anticipated): March 1, 2025
• Study Completion (Anticipated): March 1, 2025

Study Registration Dates

• First Submitted: August 27, 2019
• First Submitted That Met QC Criteria: August 27, 2019
• First Posted (Actual): August 29, 2019

Study Record Updates

• Last Update Posted (Actual): March 28, 2023
• Last Update Submitted That Met QC Criteria: March 26, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Carotid Artery Diseases; Hyperlipidemias; Dyslipidemias; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Inflammation; Carotid Stenosis; Hypercholesterolemia; Atherosclerosis; Hyperlipoproteinemia Type II; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Gout Suppressants; Colchicine
• Other Study ID Numbers: A095007 (PIILL)

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