Plasmonic Photothermal and Stem Cell Therapy of Atherosclerosis Versus Stenting

NCT01436123 | Terminated Phase 1 DMC

• 1 other identifier: NANOM PCI
• Study Type: interventional
• Target: 62
• Locations: 2 countries
• Sites: 3

Brief Summary

Intensive therapy with rosuvastatin 40 mg and ApoA-I Milano reduces the total atheroma volume (TAV) up to 6.38 or 14.1 mm3 respectively. Our previous bench studies PLASMONICS and NANOM First-in-Man trial documented TAV reduction up to unprecedented 79.4 and 60.3 mm3 respectively with high level of safety and feasibility. The completed randomized two arm (1:1) study (NANOM-PCI) with parallel assignment (n=62) assessed (NCT01436123) the safety and feasibility of the delivery technique for nanoparticles (NP) using micro-injection catheter (with intravascular intramural injection of allogeneous stem cells carrying NP after MSCT-, IVUS- and OCT-guided mapping of the vessel), and plasmonic photothermal therapy of atherosclerosis combined with stenting (Nano group, n=32) versus stenting with Xience V cage (Stenting group, n=30). The primary outcome was TAV at 12 months. The mean reduction of TAV at 12 months in Nano group was -84.1 mm3 (95% CI: SD 28.3; min -52.4 mm3, max -99.1 mm3; p\<0.05) versus +12.4 mm3 in case of stenting (p\<0.05 between groups). 42/62 patients (68%) in Nano group passed the Glagov threshold of a 40% plaque burden with mean plaque burden (PB) 36.2% (95% CI: SD 9.3%, min 30.9%, max 44.5%). The increase of the minimal lumen diameter was 61.2 and 63.3% at 12 month follow up in groups respectively. The serial assessment of VH-IVUS showed a significant decrease at 12 months in the dense calcium area, fibrous and fibro-fatty tissue with fulminant necrosis due to thermolysis in Nano-group, whereas an increase of fibrous and fibro-fatty components in stenting arm. We have documented 2 vs 3 cases of the definite thrombosis and 3 vs 5 cases of target lesion revascularization in groups respectively. The analysis of the event-free survival of the ongoing clinical follow-up shows the significantly lower risk of cardiovascular death in Nano group if compare with conventional stenting (93.4% vs 86.7%; p\<0.05). Plasmonic resonance-mediated therapy using noble-metal NP associated with significant regression of coronary atherosclerosis. Tested delivery approach has acceptable safety and efficacy for atheroregression below a 40% PB. The investigators hypothesize that multistep approach with the use of stent in acute care unit, and then subsequent transcatheter micro-injection with nanoparticles can resolve atherosclerosis, stop and regress atherogenesis, remodulate or even rejuvenate arteries. Stem cells in patch can be good carriers for nanoparticles as well as high-effective metabolic vectors (paracrine-like regulation of alive cells and via bioactive products of cell lysis after detonation of nanoparticles) for the treatment of plaque on site. Gold nanoparticles with silica-iron oxide shells promise high-energy plasmonic photothermic burning or melting effect under the near-infrared laser irradiation onto the lesion. Thus the investigators expect complex two-side effect on the plaque with protected lumen and adventitia. Novel discoveries in atherogenesis, and development of nanobiotechnologies with potentials for the management of atherosclerosis leads us to the quest of new approaches. The investigators still cannot really effectively treat atherosclerosis. The investigators management is more symptomatic, and lipid-pool or inflammation-oriented! The investigators cannot manage non-organic part (mineral deposits, calcified necrotic core, partially collagen and fibrotic tissue) and total plaque volume Surgery and invasive procedures is just focused on blood flow restoration (just manipulate the form of plaque) + concerns of clinical and technical restrictions (incl. alien body - stent) + risk of restenosis or subacute 'fatal' in-stent atherothrombosis + graft survival/ occlusion + surgery-related complications High rate of short- and long-term complications and readmissions. Regression of atherosclerosis in fact is still a dream. The investigators offer an alternative to stenting and may be cardiac artery bypass surgery (CABG). Our approach can really allow to rejuvenate arteries, Plasmonic photothermal therapy (PPTT) can burn plaque, but stem cells and bioengineered structures promise restoration of the vessel wall. Our personal previous data showed that PPTT can 1.6-fold reduce a volume of plaque with most optimal long-term result in subsets with the use of SPCs as a delivery approach. The most optimal delivery systems of NPs into the plaque are the on-artery bioengineered patch and ferro-magnetic approach.

Conditions

Coronary Artery Disease; Atherosclerosis

Keywords

Plasmonic Photothermal Therapy; Nanoparticles; Stem cells; Atherosclerosis; Bioengineering; Biodegradable stenting; Repair disease

Outcome Measures

Primary Outcomes (1)

• Total atheroma volume

  Total plaque volume measured by intravascular ultrasound (IVUS), cubic mm.

  at month 12

Secondary Outcomes (9)

• Composite end-point of any MACE (major acute cardiovascular events), all-cause death, any revascularization

  at month 12

• Composition of plaque

  at month 12

• Major and minor bleeding

  at month 12

• Restenosis rate

  at month 12

• Stent thrombosis rate

  at month 12

Study Arms (2)

Stenting + Micro-infusion

EXPERIMENTAL

Step 1 - implantation of everolimus-eluting stent with imaging by MSCT, IVUS and OCT; Step 2 - injection of stem cells containing gold nanoparticles with silica-iron oxide shells.

Other: Stenting and micro-infusion of NP

Stenting

ACTIVE COMPARATOR

Put in everolimus-eluting stent

Device: Implantation of everolimus-eluting stent

Interventions

Stenting and micro-infusion of NP OTHER

Step 1 - IVUS, OCT-guided put in everolimus-eluting (drug-eluting-DES) stent + intravascular ultrasound (IVUS) mapping + harvesting stem cells with mesenchymal phenotype; Step 2 - culturing of stem cells in medium by gold nanoparticles with silica-iron oxide shells; Step 3 - micro-infusion of stem cells bearing NP into the lesion; Step 4 - detonation of nanoshells after migration of stem cells with NPs inside (until 7-10 days after transplantation). We expect 'melting' and 'burning' effects of PPTT, beneficial effects of bioactive products of stem cells lysis + benefits from further migration of stem cells from patch into the plaque

Also known as: Plasmonic Photothermal Therapy (PPTT), Stem cell therapy, Bioengineering, Stenting, Xience V stent

Stenting + Micro-infusion

Implantation of everolimus-eluting stent DEVICE

Put stent in ischemia-related coronary artery by indications for PCI

Also known as: Stenting, Xience V stent

Stenting

Eligibility Criteria

• Age: 45 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Multivessel coronary artery disease without indications for CABG
• Stable angina with indications for preventive PCI
• NSTEMI (primary PCI and late comers) \<=\> 12 hr
• STEMI with kept EF\>50% (all comers)
• Rescue PCI
• Vessel size between 2.3-4.0 mm
• NYHA II-III functional class of HF
• De novo treatment = no history of PCI or CABG
• Atherosclerosis of proximal left anterior descending artery \<50% stenosis
• Treated hypertension
• Signed written informed consent

You may not qualify if:

• History of MI
• History of CABG or PCI
• Indications for CABG
• Contraindications for CABG, PCI
• History of unstable angina, coronary artery syndrome
• History of arrhythmias
• History of stroke
• NYHA I, IV functional class of HF
• Diabetes (fasting glucose \> 7.0 mM/L)
• Untreated hypertension
• Asthma
• Participation to any drug-investigations during previous 60 days
• Pregnancy
• Intolerance to any limus drugs, aspirin, clopidogrel, aspirin, metals and polymers of stent and nanoparticles
• Need for chronic treatment with anti-vitamin K drugs

Sponsors & Collaborators

• Ural State Medical University: lead
• Ural Institute of Cardiology: collaborator
• De Haar Research Foundation: collaborator
• Ural Federal University: collaborator

Study Sites (3)

De Haar Research Foundation

Rotterdam, South Holland, 3071PR, Netherlands

Location

Ural Center of Modern Nanotechnologies, Institute of Natural Sciences, Ural Federal University

Yekaterinburg, Sverdlovsk Oblast, 620000, Russia

Location

Ural Institute of Cardiology

Yekaterinburg, Sverdlovsk Oblast, 620144, Russia

Location

Related Publications (1)

• Kharlamov AN. Plasmonic photothermal therapy for atheroregression below Glagov threshold. Future Cardiol. 2013 May;9(3):405-25. doi: 10.2217/fca.13.16.

  PMID: 23668744 BACKGROUND

Related Links

• Ural Institute of Cardiology
• Ural State Medical Academy
• Nanocenter of the Ural Federal University

MeSH Terms

Conditions

Coronary Artery Disease; Atherosclerosis

Interventions

Stents; Bioengineering

Condition Hierarchy (Ancestors)

Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases

Intervention Hierarchy (Ancestors)

Prostheses and Implants; Equipment and Supplies; Engineering; Technology, Industry, and Agriculture

Study Officials

• Alexander Kharlamov, M.D., Ph.D.

  Ural Institute of Cardiology

  PRINCIPAL INVESTIGATOR

• Jan Gabinsky, M.D., Ph.D.

  Ural Institute of Cardiology

  STUDY CHAIR

• Olga Kovtun, M.D., Ph.D.

  Ural State Medical University

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Research manager

Study Record Dates

• First Submitted: September 14, 2011
• First Posted: September 19, 2011
• Study Start: December 1, 2010
• Primary Completion: July 1, 2012
• Study Completion: October 1, 2012
• Last Updated: May 19, 2015

Record last verified: 2015-05

Locations

NL (1); RU (2)