A Proof of Concept Study to Determine the Local Delivery and Efficacy of Intravenously Injected PEG-liposomal Prednisolone Sodium Phosphate (Nanocort) in Atherosclerotic Tissue in Subjects With Peripheral Artery Disease.
18 Years
N/A
Both
Atherosclerosis
Trial Information
A Proof of Concept Study to Determine the Local Delivery and Efficacy of Intravenously Injected PEG-liposomal Prednisolone Sodium Phosphate (Nanocort) in Atherosclerotic Tissue in Subjects With Peripheral Artery Disease.
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. Nowadays, most therapeutic interventions aimed at lowering CVD have thus far
focused on modulating lipid levels, either lowering LDLc or increasing HDLc levels. Yet,
since the introduction of statins 20 years ago, there have been few breakthroughs in the
treatment of this disease. In fact, the recent failure of a potent HDL-increasing drug, i.e.
torcetrapib, has emphasized the need to also consider non-lipid modulating targets.
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 and
prolonged efficacy and low systemic burden 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 (prolonged)
efficacy of liposomal corticosteroids at the inflammatory sites, such as atherosclerosis,
and at local macrophages remains to be determined in humans.
Thus, local delivery and prolonged efficacy can be very important tools to overcome the
potential drawback anti-inflammatory drugs; namely an inappropriate immune suppression. To
proof this concept, the investigators need to evaluate the local delivery and efficacy at
the site of inflammation (atherosclerosis) of intravenously administered liposomal
glucocorticoids (Nanocort) compared to free glucocorticoids (Prednison). Only by comparing
these two drugs, the investigators can prove the potential benefits of nanomedicine as a
vehicle for local drug delivery. This can have major implications in future drug strategies
for cardiovascular disease.
In the present project, the investigators therefore aim to evaluate the delivery and
superior efficacy of Nanocort above Prednison or placebo in patients with peripheral artery
disease due to atherosclerosis. Because these patients will undergo an endarteriectomy the
investigators will be able to collect atherosclerotic material after drug administration and
thus evaluate the local delivery and compare the effects of Nanocort to Prednison or
Placebo.
Inclusion Criteria:
- Patients must meet the following criteria for study entry:
1. Patients who are 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:
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.
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.
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Endpoint Classification: Bio-availability Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Outcome Measure:
Quantity of PEG liposomes in the atherosclerotic plaque and/ or in atherosclerotic macrophages as determined with a PEG antibody quantitative sandwich ELISA.
Outcome Description:
Quantity of PEG liposomes in the atherosclerotic plaque and/ or in atherosclerotic macrophages as determined with a PEG antibody quantitative sandwich ELISA.
Outcome Time Frame:
Participation of patient: maximally 12 days (infusion 1 on day-10 (+/-2days), infusion 2 on day-3, operation and sample collection on day 0) Data assessment: average 4 months.
Safety Issue:
No
Principal Investigator
E S Stroes, MD PhD
Investigator Role:
Principal Investigator
Investigator Affiliation:
AIDS Malignancy Clinical Trials Consortium
Authority:
Netherlands: Medical Ethics Review Committee (METC)
Study ID:
NL39717.018.12
NCT ID:
NCT01647685
Start Date:
May 2012
Completion Date:
May 2013
Related Keywords:
- Atherosclerosis
- Vesselwall inflammation
- liposomal prednisolone
- Atherosclerosis
- Peripheral Arterial Disease
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