Primary1. To demonstrate that 89Zr-CER-001 penetrates into atherosclerotic plaques in patients by means of PET imaging. Secondary 2. To evaluate whether the amount of 89Zr-CER-001 penetrating the plaque corresponds to athero-lesion severity.3. To…
ID
Source
Brief title
Condition
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
89Zr-CER-001 uptake in the plaque over time, reported as Standardized Uptake
Value (SUV), by means of PET imaging.
Secondary outcome
Further quantification of CER-001 uptake at the plaque
- 89Zr-CER-001 uptake in the plaque over time assessed as the Target to
Background Ratio (TBR), via PET imaging
- Difference between SUV and TBR at the level of the plaque and SUV and TBR of
non-diseased arterial wall on PET
Relation between CER-001 uptake and plaque characteristics
- Relation between SUV and TBR of the plaque on PET and structural plaque
dimensions on MRI i.e. normalized wall index, vessel wall area. - Relation
between SUV and TBR of the plaque and plaque permeability on DCE-MRI, i.e.
Ktrans
Relationship between the CER-001 uptake in the plaque by means of PET imaging
reported as SUV of the plaque and the cholesterol efflux capacity.
Background summary
Atherosclerosis is considered a chronic inflammatory disease in which
macrophages play a major role by taking up (oxidized) low-density lipoprotein
(LDL). The lipid-laden macrophages accumulate and undergo apoptosis leading to
the formation of a necrotic core and eventually the vulnerable plaque.
Cholesterol efflux from lipid-laden macrophages is a key atheroprotective
mechanism, a process referred to as reverse cholesterol transport (RCT) in
which apolipoprotein (apo)A-1 and HDL particles remove cholesterol from
peripheral cells. In view of the abundant evidence for apoA-1 on stimulating
efflux from macrophages in vitro, it is reasonable to assume that apoA-1 will
also stimulate efflux from vessel wall macrophages in vivo if apoA-1 succeeds
in getting into the proximity of plaque macrophages.
The radio-isotope Zirconium-89 (89Zr) has emerged as a *gold-standard* in the
field of antibody-based PET imaging. The experience in oncology and the fact
that 89Zr-labeling is a GMP-approved method makes this a suitable candidate for
proving target delivery of apoA-1/HDL into advanced atherosclerotic plaques in
humans using non-invasive imaging techniques. With this project we aim to show
that exogenously infused apoA-1 (CER-001®) penetrates into advanced plaques in
patients, making it *highly likely* that efflux of cholesterol from macrophages
to the apoA-1/HDL complex will occur.
Study objective
Primary
1. To demonstrate that 89Zr-CER-001 penetrates into atherosclerotic plaques in
patients by means of PET imaging.
Secondary
2. To evaluate whether the amount of 89Zr-CER-001 penetrating the plaque
corresponds to athero-lesion severity.
3. To evaluate whether the amount of 89Zr-CER-001 penetrating the plaque
corresponds to plaque permeability.
4. To evaluate whether the amount of 89Zr-CER-001 penetrating the plaque
corresponds to the cholesterol efflux capacity
Study design
This study is designed as a single-center, observational study. Patients with a
very high cardiovascular risk and signs of atherosclerotic lesions in the
ascending aorta or carotid arteries (evaluated using ultrasound and/or MRI)
will be subjected to a (DCE-) MRI. Subsequently, 89Zr labelled CER-001 (3mg/kg)
is infused (18Mbq) where after low-dose PET/CT of the aorta and carotid
arteries is performed. Starting with a PET/CT-scan 10 minutes after infusion
followed by a scan at 24 and 72 hours after.
Study burden and risks
The results of this study will add to our understanding on the role of CER-001
as an anti-atherosclerotic strategy: if CER-001 accesses the atherosclerotic
lesion, it is highly likely that CER-001 is able to induce efflux from
cholesterol-laden macrophages within atherosclerotic lesions. Patients receive
no direct benefits, however these research results will increase the likelihood
of CER-001 to enter a clinical development program targetting regression of
severe atherosclerosis in patients with similar critera as those inncluded in
the present study. The maximum radiation exposure of the infusion of 89Zr
-labeled CER-001 and 3 sequential low-dose CT scans is 18 mSv
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
Patients must meet the following criteria for study entry:
- Adult patients (either gender) * 50 years
- Documented atherosclerotic vascular disease; defined as carotid artery stenosis > 50% on clinical MRI or ultrasound.
- Clinically stable for at least 3 months prior to inclusion
Exclusion criteria
Patients are not eligible if they meet one of the criteria listed below:
- Creatinine clearance < 50 ml/min (MDRD) 6 months prior to inclusion
- Auto-immune disease/vasculitis, other active inflammatory diseases, proven or suspected bacterial infections. Recent (< 1 month prior to inclusion) or ongoing serious infection requiring IV antibiotic therapy that could interfere with the conduct of the study in the opinion of the investigator
- Known systemic disorders such as hepatic, renal, hematologic, and malignant diseases or any clinically significant medical condition that could interfere with the conduct of the study in the opinion of the investigator
- Standard contra-indications to MRI, PET, and CT
- Inability or unwillingness to comply with the protocol requirements, or deemed by investigator to be unfit for the study
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-001666-10-NL |
| CCMO | NL49081.018.14 |
| OMON | NL-OMON22856 |