1. To proof local delivery of intravenously administered liposomal glucocorticoids (Nanocort) in subjects with peripheral artery disease by demonstrating Nanocort in atherosclerotic tissue. 2. To determine the differences between cytokine production…
ID
Source
Brief title
Condition
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Quantity of PEG liposomes in the atherosclerotic plaque and/ or in
atherosclerotic macrophages as determined with a PEG antibody quantitative
sandwich ELISA.
Secondary outcome
Differences in concentration of corticosteroids in the atherosclerotic plaque
and/or in atherosclerotic macrophages.
Differences between TNF-alpha levels in the supernatant of isolated macrophages
from the atherosclerotic tissue as determined by quantitative sandwich ELISA
Background summary
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in
developed nations. CVD is primarily caused by atherosclerosis, a systemic
disease characterized by lipid deposition in the subendothelial space with a
concomitant, low-grade inflammatory reaction.
A promising strategy to reduce CVD is to directly target inflammation at the
level of the vessel wall. A potential drawback of anti-inflammatory strategies
pertains to the thin line between inhibiting *inappropriate* inflammation
versus inducing immuno-suppression. One of the strategies to limit systemic
immunosuppression is to strive for local delivery of the drug by encapsulating
the compound in liposomes.
Liposome-encapsulated drugs efficiently target lesions and accumulate at a much
higher extent at desired areas of interest. This approach is currently used for
the clinical treatment of different types of cancer (liposomal doxorubicin) and
fungal infections (liposomal amphotericine-B). Liposomes for other applications
(rheumatoid arthritis, cystic fibrosis, multiple sclerosis and atherosclerosis)
are being pre-clinically developed or investigated in clinical trials.
Recent pre-clinical studies in animal models corroborate that liposomal
glucocorticoids effectively attenuate atherosclerotic plaque inflammation and
exhibit improved pharmacokinetics and biodistribution. Also, local delivery
through localization of liposomes at inflammatory sites and in local
macrophages was demonstrated in animal models.
In humans, the potential of PEG-liposomes to target inflammatory sites has been
showed by imaging of radioactive liposomes.
However, the concept of local delivery and efficacy of liposomal
corticosteroids at the inflammatory sites, such as atherosclerosis, and at
local macrophages remains to be determined in humans. In the present project,
we aim to evaluate the delivery and efficacy of intravenously administered
liposomal glucocorticoids (Nanocort) compared to systemic infused
corticosteroids or placebo in patients with peripheral artery disease.
Study objective
1. To proof local delivery of intravenously administered liposomal
glucocorticoids (Nanocort) in subjects with peripheral artery disease by
demonstrating Nanocort in atherosclerotic tissue.
2. To determine the differences between cytokine production of isolated
atherosclerotic macrophages from patients with peripheral artery disease
treated with liposomal glucocorticoids (Nanocort), systemic glucocorticoids
(Methylprednisone) or placebo.
Study design
A proof-of-concept, multi-center(AMC en Flevoziekenhuis), randomized,
placebo-controlled study evaluating the concept of local delivery of
intravenously injected PEG-liposomal prednisolone sodium phosphate (Nanocort)
versus Methylprednisolone or placebo in subjects scheduled for operation due to
peripheral artery disease.
Intervention
Subjects will be randomized to either Nanocort, Methylprednisolone or placebo
(saline) infusion using a 1:1 ratio on day 10±1 and day 3 ±1 before the
operation date.
Study burden and risks
The results of this study contribute to the development of novel
anti-inflammatory directed atherosclerotic treatment strategies. Patients
receive no direct benefits.
Patients should visit the AMC or Flevoziekenhuis 2 times, besides the day of
their scheduled endarterectomy. There are 2 infusions of Nanocort,
Methylprednisolone or placebo, patients may experience these infusions as a
burden.
Meibergdreef 9
1105AZ
NL
Meibergdreef 9
1105AZ
NL
Listed location countries
Age
Inclusion criteria
Patients must meet the following criteria for study entry: ;1) Patients scheduled for endarterectomy due to peripheral artery disease.;2) If using a statin, on stable therapy for at least 6 weeks prior to screening with no evidence of statin intolerance.;3) For patients taking angiotensin-converting enzyme (ACE) inhibitors (ACE-I) or angiotensin-receptor blockers (ARBs), non-statin lipid-modifying therapy, thiazolidinediones, inhaled steroids, or leukotriene modifying agents, use of a stable dose for at least 6 weeks prior to baseline measurement.;4) For patients taking Nonsteroidal anti-inflammatory drugs (NSAIDS), Cyclo-oxygenase-2 inhibitors (COXIBs), use of a stable dose for at least 6 weeks prior to baseline measurement.
Exclusion criteria
Subjects may not enter this study if they meet the following criteria: ;1) Current medical history of Auto-immune disease/vasculitis, active inflammatory diseases, proven or suspected bacterial infections. Recent (<1 month prior to screening) or ongoing serious infection requiring IV antibiotic therapy. ;2) Recent or current treatment with medications that may have a significant effect on plaque inflammation, including but not limited to: ;* Steroids for at least 6 weeks prior to baseline measurement and during study (with the exception of inhaled steroids).;* Biological based medicines (anti-TNF (ex. Infliximab), anti-IL-6 therapy (ex. Tocilizumab) or anti-IL-1 (ex. anakinra)) within 8 weeks before the baseline visit and during the study;* No other Disease modifying antirheumatic drugs (DMRADS) within 6 weeks of baseline and during study (such as cyclosporine, azatioprine, etc.);3) Known systemic disorder, such as hepatic, renal, hematologic or endocrine diseases, infections or malignancies, or any clinically significant medical condition that could interfere with the conduct of the study. ;4) Subjects with a known ulcus ventriculi or duodeni.;5) Female subjects who are breastfeeding, pregnant or trying to get pregnant. ;6) History of anaphylaxis, anaphylactoid (resembling anaphylaxis) reactions, or severe allergic responses.;7) History of hypersensitivity to methylprednisolone or any component of the formulation.;8) Any history of myopathy or a history of neuromuscular disorders (e.s, myasthenia gravis).;9) Any planned vaccinations.;10) Inability or unwillingness to comply with the protocol requirements, or deemed by investigator to be unfit for the study.;11) Subject has planned cardiac surgery, PCI or carotid stenting, or major non-cardiac surgery during the course of the study period or for 14 days after the last treatment. Subjects scheduled for endarterectomy are not excluded.
12) Current medical history of drug or alcohol abuse within 12 months prior to screening.;13) Subjects are not permitted to enter the study if they have taken any investigational drug in the 3 months prior to study drug administration.
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
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-000543-27-NL |
| CCMO | NL39717.018.12 |