PIILL: PET Imaging of Inflammation and Lipid Lowering Study
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
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 stable cardiovascular disease or heterozygous familial hypercholesterolemia (HeFH) and elevated low density lipoprotein (LDL) cholesterol despite high-intensity statin treatment will undergo serial carotid 68Ga-DOTATATE PET-magnetic resonance imaging (MRI) in a double-blind, two-arm, parallel-design, placebo-controlled study.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Stable CVD - treatment Stable CVD with elevated LDL cholesterol despite high-intensity atorvastatin, randomised to add on therapy with a PCSK9 inhibitor |
Drug: PCSK9 inhibitor
PCSK9 inhibitor
Other Names:
Diagnostic Test: 68Ga-DOTATATE PET-MRI
68Ga-DOTATATE PET-MRI at baseline and 12 weeks
|
| Placebo Comparator: Stable CVD - placebo control Stable CVD with elevated LDL cholesterol despite high-intensity atorvastatin, randomised to placebo control |
Diagnostic Test: 68Ga-DOTATATE PET-MRI
68Ga-DOTATATE PET-MRI at baseline and 12 weeks
|
| Experimental: HeFH - treatment HeFH and elevated LDL cholesterol despite high-intensity atorvastatin, randomised to add on therapy with a PCSK9 inhibitor |
Drug: PCSK9 inhibitor
PCSK9 inhibitor
Other Names:
Diagnostic Test: 68Ga-DOTATATE PET-MRI
68Ga-DOTATATE PET-MRI at baseline and 12 weeks
|
| Placebo Comparator: HeFH - placebo control HeFH and elevated LDL cholesterol despite high-intensity atorvastatin, randomised to placebo control |
Diagnostic Test: 68Ga-DOTATATE PET-MRI
68Ga-DOTATATE PET-MRI at baseline and 12 weeks
|
Outcome Measures
Primary Outcome Measures
- Carotid 68Ga-DOTATATE PET [12 weeks]
Relative change from baseline in carotid artery 68Ga-DOTATATE tissue-to-blood ratio in the index vessel
Secondary Outcome Measures
- Carotid 68Ga-DOTATATE vs. MRI [12 weeks]
Comparison of carotid artery 68Ga-DOTATATE imaging to changes in plaque morphology assessed by high-resolution carotid MRI
- Carotid 68Ga-DOTATATE vs. serum lipids [12 weeks]
Comparison of carotid 68Ga-DOTATATE imaging to serum lipids
- Carotid 68Ga-DOTATATE vs. hsCRP [12 weeks]
Comparison of carotid 68Ga-DOTATATE imaging to high-sensitivity C-reactive protein (hsCRP)
Eligibility Criteria
Criteria
Inclusion Criteria:
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Male or female participants >18 years old
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Able to give written, informed consent and to lie flat
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Have a history of CVD (acute coronary syndrome, ischaemic stroke, transient ischaemic attack, or documented coronary, carotid, or peripheral arterial disease) and elevated LDL cholesterol despite high-intensity atorvastatin (Group 1), or
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Have HeFH (definite or probable FH based on clinical criteria) and elevated LDL cholesterol despite high-intensity atorvastatin (Group 2)
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Lipid lowering therapy unchanged for at least 6 weeks prior to screening
Exclusion Criteria:
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Women of child bearing potential not using adequate contraception
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Contra-indication to MRI scanning
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Statin-associated myositis or liver function abnormality
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Sensitivity to PCSK9 inhibitors or monoclonal antibodies
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Contrast allergy or contrast-nephropathy
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Chronic kidney disease (eGFR <30 mL/min/1.73 m2)
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Cardiovascular event within 6 months
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Any medical condition, in the opinion of the investigator, that prevents the participant from lying flat during scanning, or from participating in the study
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Uncontrolled chronic inflammatory disorder
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History of recent malignancy deemed relevant to the study by the investigator
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Treatment with medications that result in significant drug to drug interactions with the study medication
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Current use of systemic corticosteroids
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Previous carotid endarterectomy surgery or stenting
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Cambridge | Cambridge | United Kingdom |
Sponsors and Collaborators
- University of Cambridge
- Cambridge University Hospitals NHS Foundation Trust
- Wellcome Trust
Investigators
- Principal Investigator: Jason M Tarkin, MBBS PhD, University of Cambridge
Study Documents (Full-Text)
None provided.More Information
Publications
- Pedersen SF, Sandholt BV, Keller SH, Hansen AE, Clemmensen AE, Sillesen H, Højgaard L, Ripa RS, Kjær 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.
- 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 (68)Ga-DOTATATE PET Compared to [(18)F]FDG PET Imaging. J Am Coll Cardiol. 2017 Apr 11;69(14):1774-1791. doi: 10.1016/j.jacc.2017.01.060.
- A095007 (PIILL)