Silencing Inflammatory Activity by Injecting Nanocort in Patients at Risk for Atherosclerotic Disease (SILENCE)

A Phase I/II, Single-Center, Randomized, Placebo-Controlled Study Evaluating the Therapeutic Efficacy of Intravenously Injected PEG-liposomal Prednisolone Sodium Phosphate (Nanocort®) in Subjects With Severe Inflamed Carotid or Aortic Atherosclerosis Plaques

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.(Fuster, Moreno et al. 2005) To date, 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. A promising strategy to reduce CVD is to directly target inflammation at the level of the vessel wall.(van Leuven, van Wijk et al.; Libby 2002) A potential drawback of anti-inflammatory strategies pertains to the thin line between inhibiting 'inappropriate' inflammation versus inducing immuno-suppression. Therefore, continuous low dosed anti-inflammatory drugs have great potential as novel treatment strategies. In the present project, the investigators propose to inject liposomal glucocorticoids intravenously in patients with an increased risk of atherosclerotic disease aiming to reduce vessel wall inflammation.

Study Overview

• Status: Unknown
• Conditions: Inflammation; Atherosclerosis
• Intervention / Treatment: Drug: Placebo; Drug: liposomal prednisolone

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1105AZ
    • Recruiting
    • Academic Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Population with target to background ratio of 2.2 of the aorta or carotid artery on PET-CT

Exclusion Criteria:

• Current medical history of auto-immune disease/vasculitis, active inflammatory diseases, 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 as measured by plaque TBR, including but not limited to:

  • Steroids for at least 6 weeks prior to baseline measurement and during study (with the exception of inhaled acute use 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 disorders such as hepatic, renal, hematologic, and malignant diseases or any clinically significant medical condition that could interfere with the conduct of the study.
• Changes in dose or frequency of doses at least 6 weeks prior to baseline measurement (unstable dosing) in angiotensin-converting enzyme (ACE) inhibitors (ACE-I) or angiotensin-receptor blockers (ARBs), non-statin lipid-modifying therapy, thiazolidinediones, inhaled steroids, or leukotriene modifying agents, nonsteroidal anti-inflammatory drugs (NSAIDS), and cyclo-oxygenase-2 inhibitors (COXIBs)
• Standard contra-indications to MRI, 18FDG PET, and CT based on physicians experience and current practices
• Current medical history of poorly controlled diabetes defined as hemoglobin A1c (HbA1c) >7.5%.
• Current medical history of drug or alcohol abuse within 12 months prior to screening.
• History of anaphylaxis, anaphylactoid (resembling anaphylaxis) reactions, or severe allergic responses.
• 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.
• Use of any investigational drug in the 3 months prior to study drug administration.
• Use of insulin or any oral anti-diabetic (except metformin) in the 30 days prior to baseline measurements. Those subjects who are taking metformin may be included in the study if they are on a stable dose for at least 4 weeks and have a HbA1c <7.5%.
• Any contraindications for corticosteroid infusions (for example, but not limited current infections or vaccinations)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Liposomal prednisolone	Drug: liposomal prednisolone; Two weekly dosages with 150 mg.
Placebo Comparator: Placebo control	Drug: Placebo; Drug: liposomal prednisolone; Two weekly dosages with 150 mg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
18Fludeoxyglucose Positron emission computed tomography scan (18FDG PET-CT scan)	Day 8-13

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Investigators: Principal Investigator: Erik S Stroes, MD PhD, AIDS Malignancy Consortium

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (Anticipated): May 1, 2013

Study Registration Dates

• First Submitted: October 13, 2011
• First Submitted That Met QC Criteria: May 16, 2012
• First Posted (Estimate): May 17, 2012

Study Record Updates

• Last Update Posted (Estimate): May 21, 2012
• Last Update Submitted That Met QC Criteria: May 18, 2012
• Last Verified: May 1, 2012

More Information

Terms related to this study

• Keywords: Atherosclerosis, inflammation
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Inflammation; Atherosclerosis; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antineoplastic Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Prednisolone
• Other Study ID Numbers: NL37190.018.11