PET Imaging of Inflammation and Lipid Lowering Study

NCT ID: NCT04073797

Last Updated: 2024-07-19

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 63 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-03-20
• Study Completion Date: 2026-03-01

Brief Summary

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

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.

Conditions

Hypercholesterolemia; Hypercholesterolemia, Familial; Atherosclerosis; Carotid Artery Plaque

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: QUADRUPLE

Study Groups

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

Group Type: EXPERIMENTAL

Inclisiran

Intervention Type: DRUG

Inclisiran 284 mg, one injection

68Ga-DOTATATE PET-MRI

Intervention Type: DIAGNOSTIC_TEST

68Ga-DOTATATE PET-MRI at baseline and 12 weeks

Stable CVD - placebo control

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

Group Type: ACTIVE_COMPARATOR

68Ga-DOTATATE PET-MRI

Intervention Type: DIAGNOSTIC_TEST

68Ga-DOTATATE PET-MRI at baseline and 12 weeks

Colchicine

Intervention Type: DRUG

Colchicine 500 mcg tablet once daily

HeFH - treatment

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

Group Type: PLACEBO_COMPARATOR

Inclisiran

Intervention Type: DRUG

Inclisiran 284 mg, one injection

68Ga-DOTATATE PET-MRI

Intervention Type: DIAGNOSTIC_TEST

68Ga-DOTATATE PET-MRI at baseline and 12 weeks

Interventions

Inclisiran

Inclisiran 284 mg, one injection

Intervention Type: DRUG

68Ga-DOTATATE PET-MRI

68Ga-DOTATATE PET-MRI at baseline and 12 weeks

Intervention Type: DIAGNOSTIC_TEST

Colchicine

Colchicine 500 mcg tablet once daily

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Cambridge University Hospitals NHS Foundation Trust

OTHER

Sponsor Role: collaborator

Wellcome Trust

OTHER

Sponsor Role: collaborator

GE Healthcare

INDUSTRY

Sponsor Role: collaborator

Lund University

OTHER

Sponsor Role: collaborator

University of Cambridge

OTHER

Sponsor Role: lead

Responsible Party

Jason Tarkin

Wellcome Clinical Research Career Development Fellow & Honorary Consultant Cardiologist

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jason M Tarkin, MBBS PhD

Role: PRINCIPAL_INVESTIGATOR

University of Cambridge

Locations

University of Cambridge

Cambridge, , United Kingdom

Site Status: RECRUITING

Countries

United Kingdom

Central Contacts

Jason M Tarkin, MBBS PhD

Role: CONTACT

jt545@cam.ac.uk

+44(0)1223331504

Facility Contacts

Jason M Tarkin, MBBS PhD

Role: primary

jt545@cam.ac.uk

+44(0)1223331504

References

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.

Reference Type: BACKGROUND

PMID: 28385306 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25977567 (View on PubMed)

Other Identifiers

A095007 (PIILL)

Identifier Type: -

Identifier Source: org_study_id