PET Imaging of Inflammation and Lipid Lowering Study

NCT04073797 | Recruiting

• 1 other identifier: A095007 (PIILL)
• Study Type: interventional
• Target: 63
• Locations: 1 country
• Sites: 1

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.

Conditions

Hypercholesterolemia; Hypercholesterolemia, Familial; Atherosclerosis; Carotid Artery Plaque

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (3)

• MRI plaque burden

  12 weeks

• Carotid 68Ga-DOTATATE vs. serum lipids

  12 weeks

• Carotid 68Ga-DOTATATE vs. hsCRP

  12 weeks

Study Arms (3)

Stable CVD - treatment

EXPERIMENTAL

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; Diagnostic Test: 68Ga-DOTATATE PET-MRI

Stable CVD - placebo control

ACTIVE COMPARATOR

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; Drug: Colchicine

HeFH - treatment

PLACEBO COMPARATOR

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

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

Interventions

Inclisiran DRUG

Inclisiran 284 mg, one injection

HeFH - treatment; Stable CVD - treatment

68Ga-DOTATATE PET-MRI DIAGNOSTIC_TEST

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

HeFH - treatment; Stable CVD - placebo control; Stable CVD - treatment

Colchicine DRUG

Colchicine 500 mcg tablet once daily

Stable CVD - placebo control

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Cambridge: lead
• Cambridge University Hospitals NHS Foundation Trust: collaborator
• Wellcome Trust: collaborator
• GE Healthcare: collaborator
• Lund University: collaborator

Study Sites (1)

University of Cambridge

Cambridge, United Kingdom

RECRUITING

Related Publications (2)

• 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.

  PMID: 28385306 BACKGROUND

• 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.

  PMID: 25977567 BACKGROUND

MeSH Terms

Conditions

Hypercholesterolemia; Hyperlipoproteinemia Type II; Atherosclerosis; Carotid Stenosis

Interventions

ALN-PCS; Colchicine

Condition Hierarchy (Ancestors)

Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hyperlipoproteinemias; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases; Carotid Artery Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Alkaloids; Heterocyclic Compounds

Study Officials

• Jason M Tarkin, MBBS PhD

  University of Cambridge

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jason M Tarkin, MBBS PhD

CONTACT

+44(0)1223331504; jt545@cam.ac.uk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blind, placebo controlled.
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Wellcome Clinical Research Career Development Fellow & Honorary Consultant Cardiologist

Study Record Dates

• First Submitted: August 27, 2019
• First Posted: August 29, 2019
• Study Start: March 20, 2023
• Primary Completion: October 1, 2025
• Study Completion: March 1, 2026
• Last Updated: July 19, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)