AtherosclerosisPhase 1/2DELIVERNCT01647685
A Proof of Concept Study to Determine the Local Delivery and Efficacy of Nanocort
A Phase 1/2 study testing Nanocort and Methylprednisolone in people with Atherosclerosis, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 1 site in Netherlands.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Atherosclerosis
- What is being tested?
- Nanocort and Methylprednisolone
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 21 participants
- Where
- 1 siteNetherlands
- Study dates
- May 2012to May 2013
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients must meet the following criteria for study entry:
- Patients who are scheduled for endarterectomy due to peripheral artery disease.
- If using a statin, on stable therapy for at least 6 weeks prior to screening with no evidence of statin intolerance.
- 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.
- 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.
Who cannot join
- 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.
- 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.)
- 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.
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- Subjects with a known ulcus ventriculi or duodeni.
- Female subjects who are breastfeeding, pregnant or trying to get pregnant.
- History of anaphylaxis, anaphylactoid (resembling anaphylaxis) reactions, or severe allergic responses.
- History of hypersensitivity to methylprednisolone or any component of the formulation.
- Any history of myopathy or a history of neuromuscular disorders (e.s, myasthenia gravis).
- Any planned vaccinations.
- Inability or unwillingness to comply with the protocol requirements, or deemed by investigator to be unfit for the study.
- 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.
- Current medical history of drug or alcohol abuse within 12 months prior to screening.
- Subjects are not permitted to enter the study if they have taken any investigational drug in the 3 months prior to study drug administration.
Trial locations and contacts
1 site in 1 country.
Netherlands1 site, 1 recruiting
- Recruiting
AMC
Amsterdam, Amsterdam, 1105AZ
F M van der Valk, MD, 0031 20 5668792, f.m.valkvander@amc.nl
E S Stroes, MD, PhD
About this study
Official title: 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.
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. Thus, local delivery and prolonged efficacy can be very important tools to overcome the potential drawback anti-inflammatory drugs; namely an inappropriate immune suppression. 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.
Read the detailed description
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.
- Conditions
- Atherosclerosis
- Being tested
- Nanocort, Methylprednisolone, Placebo
- Keywords
- Vesselwall inflammation, liposomal prednisolone
- Medical subject headings
- Atherosclerosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NanocortDrug
Also called Nanocort (PEG-liposomal prednisolone sodium phosphate).
Two weekly IV infusions of 150 mg Nanocort (PEG-liposomal prednisolone sodium phosphate).
Also called Methylprednisolone, Solu-medrol
Two weekly infusion iv methylprednisolone sodium succinate 125 mg infusion.
PlaceboDrug
Also called NaCl 0.9%
Saline solution (same solution brand as used to dilute/prepare Nanocort injection)
| Study group | Role | What they receive |
|---|---|---|
| Nanocort | Active comparator | Two weekly IV infusions of 144 mg Nanocort (PEG-liposomal prednisolone sodium phosphate). Receives: Drug: Nanocort |
| Methylprednisolone | Active comparator | Methylprednisolone sodium succinate 125 mg infusion. Receives: Drug: Methylprednisolone |
| Saline | Placebo comparator | Saline solution (same solution brand as used to dilute/prepare Nanocort injection) Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Quantity of PEG liposomes in the atherosclerotic plaque and/ or in atherosclerotic macrophages as determined with a PEG antibody quantitative sandwich ELISA.
Quantity of PEG liposomes in the atherosclerotic plaque and/ or in atherosclerotic macrophages as determined with a PEG antibody quantitative sandwich ELISA.
Measured: 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.
Secondary outcomes (2)
Differences between TNF-alpha levels in the supernatant of isolated macrophages from the atherosclerotic tissue as determined by quantitative sandwich ELISA
Differences between TNF-alpha levels in the supernatant of isolated macrophages from the atherosclerotic tissue as determined by quantitative sandwich ELISA
Measured: 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.
Concentration of corticosteroids in plaque.
Differences in concentration of corticosteroids in atherosclerotic plaque between 3 groups.
Measured: 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.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jul 2012 (estimated)
- Study startMay 2012
- Primary completionMay 2013 (estimated)
- Study completionMay 2013 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for AtherosclerosisStudies of the same condition, open and under way.
- More trials run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 21 participants (estimated)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, E.S.stroes, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
- Investigators
- E S Stroes, MD PhD, Principal investigator, AIDS Malignancy Consortium
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01647685
- Sponsor's protocol ID
- NL39717.018.12
- Acronym
- DELIVER
- Status last verified
- May 2012
- First submitted
- 28 Jun 2012
- Last updated
- 23 Jul 2012
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 23 Jul 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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.
- ClinicalTrials.gov ID
- NCT01647685
- Acronym / sponsor ID
- DELIVER / NL39717.018.12
- Conditions
- Atherosclerosis
- Keywords
- Vesselwall inflammation, liposomal prednisolone
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 21 participants (estimated)
- Lead sponsor
- Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)University, hospital or other
- Study start
- May 2012
- Primary completion
- May 2013 (estimated)
- Study completion
- May 2013 (estimated)
- First posted
- 23 Jul 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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. Thus, local delivery and prolonged efficacy can be very important tools to overcome the potential drawback anti-inflammatory drugs; namely an inappropriate immune suppression. 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.
Detailed description
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.
Study design
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Nanocort | Active comparator | Drug: NanocortTwo weekly IV infusions of 144 mg Nanocort (PEG-liposomal prednisolone sodium phosphate). |
| Methylprednisolone | Active comparator | Drug: MethylprednisoloneMethylprednisolone sodium succinate 125 mg infusion. |
| Saline | Placebo comparator | Drug: PlaceboSaline solution (same solution brand as used to dilute/prepare Nanocort injection) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Patients must meet the following criteria for study entry:
Key exclusion criteria (16 listed)
- 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.
- Recent or current treatment with medications that may have a significant effect on plaque inflammation, including but not limited to:
- 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.
- Subjects with a known ulcus ventriculi or duodeni.
- Female subjects who are breastfeeding, pregnant or trying to get pregnant.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NanocortAlso: Nanocort (PEG-liposomal prednisolone sodium phosphate).Two weekly IV infusions of 150 mg Nanocort (PEG-liposomal prednisolone sodium phosphate). | Drug | Nanocort |
| MethylprednisoloneAlso: Methylprednisolone, Solu-medrolTwo weekly infusion iv methylprednisolone sodium succinate 125 mg infusion. | Drug | Methylprednisolone |
| PlaceboAlso: NaCl 0.9%Saline solution (same solution brand as used to dilute/prepare Nanocort injection) | Drug | Saline |
Primary outcome
Quantity of PEG liposomes in the atherosclerotic plaque and/ or in atherosclerotic macrophages as determined with a PEG antibody quantitative sandwich ELISA.
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.
Quantity of PEG liposomes in the atherosclerotic plaque and/ or in atherosclerotic macrophages as determined with a PEG antibody quantitative sandwich ELISA.
2 secondary outcomes
Differences between TNF-alpha levels in the supernatant of isolated macrophages from the atherosclerotic tissue as determined by quantitative sandwich ELISA
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.
Concentration of corticosteroids in plaque.
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.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Jul 2012.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
E S Stroes, MD PhD principal investigator
AIDS Malignancy Consortium
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Nanocort and Methylprednisolone in people with Atherosclerosis, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 23 Jul 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact F M van der Valk, MD (0031 20 5668791, f.m.valkvander@amc.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Quantity of PEG liposomes in the atherosclerotic plaque and/ or in atherosclerotic macrophages as determined with a PEG antibody quantitative sandwich ELISA. (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.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jul 2012.