Plasmonic Nanophotothermal Therapy of Atherosclerosis

NCT01270139 | Completed Results DMC

• 1 other identifier: NANOM-FIM
• Study Type: interventional
• Target: 180
• Locations: 2 countries
• Sites: 4

Brief Summary

The investigators hypothesize that the nanoburning is a very challenging technique to demolish and reverse the plaque especially in combination with stem cell technologies promising the functional restoration of the vessel wall. The completed (in July 2012) interventional three arms (n=180) first-in-man trial (the NANOM-FIM trial) assessed (NCT01270139) the safety and feasibility of two delivery techniques for nanoparticles (NP), and plasmonic photothermal therapy (PPTT) of atherosclerotic lesions. Patients were assigned in a 1:1:1 ratio to receive either (1) nano-intervention with delivery of silica-gold NP in mini-surgery implanted bioengineered on-artery patch (n=60), or (2) nano-intervention with delivery of silica-gold iron-bearing NP with targeted micro-bubbles or stem cells in hands of magnetic navigation system (n=60) versus (3) stent implantation (n=60). The primary outcome was TAV at 12 months. The observational prospective cohort analysis (an amendment to the protocol of August 29th 2012 with a decision to extend a 1-year study for another 4 years with the assessment of the 5-year clinical outcomes both retro- and prospectively) of the long-term clinical outcomes at the intention-to-treat population of 180 patients with CAD and angiographic SYNTAX score ≤22 enrolled initially to NANOM-FIM trial will be performed at 5 years after the intervention. The primary outcome will be a MACE-free survival. The secondary outcomes will be MACE, cardiac death, TLR (target lesion revascularization) and TVR (target vessel revascularization). Imaging endpoints will be assessed pre-, post- procedure and at 12-month follow-up. Clinical endpoints will be analyzed at the baseline and at 12 and 60-month follow-up (the release of results is expected after October 2016). Parameters of nanotoxicity will be assessed. The independent adjudication analysis of the clinical outcomes is scheduled in 2017-2019. The subset post-hoc analysis will be conducted at 1- and 5-year follow-up (by the Amendment of August 29th 2012). At the first subset, patients underwent stenting with XIENCE V stent proximal to the site of nano-intervention (n=13). Subjects in the second subset were undergone drug-coated balloon pre-dilation with further nano-technique (n=20). Lesions in patients of the third subset were not prepared for the nano-approach (n=147) (neither stenting nor balloon angioplasty). The analysis will be performed and results will be released after 2018 with the same clinical outcomes. This project and related manuscripts were not prepared or funded in any part by a commercial organization. Nanoparticles and biomedical equipment were supplied free for the study by the non-profit Agiko and De Haar Research Task Force (Rotterdam-Amsterdam, the Netherlands). All rights of the authors are reserved. The access of the international academic or governmental organizations to the essential and primary data of the trial is restricted by the Russian governmental authorities due to the interest of the Russian Federal Security Service (FSB).

Conditions

Stable Angina; Heart Failure; Atherosclerosis; Multivessel Coronary Artery Disease

Keywords

nanoparticles; mesenchymal stem cell; plasmonics; atherosclerosis; IVUS; stenting

Outcome Measures

Primary Outcomes (2)

• Total Atheroma Volume

  Total atheroma volume (TAV, plaque-media volume, mm3) at 12 months. Quantitative coronary angiography (QCA) and Intravascular Ultrasound (IVUS) were performed pre-, post-procedure and at 12-month follow-up after a bolus infusion of i.c. nitrate. QCA was undergone with the CAAS II analysis system (Pie Medical B.V., Maastricht, The Netherlands) with analysis of different QCA parameters such as minimal lumen diameter, maximum lumen diameter, reference diameter, diameter stenosis, lesion length, percent atheroma volume (PAV), total atheroma volume (TAV), and lumen volume.

  at 12-month follow-up

• MACE (Major Adverse Cardiovascular Events)-Free Survival

  MACE (major adverse cardiovascular events)-free survival reflects per cent of survived patients without MACE. An amendment to the protocol was approved on August 29th 2012 with a decision to extend a 1-year study for another 4 years with the assessment of the 5-year clinical outcomes both retro- and prospectively.

  at 60 months follow-up

Secondary Outcomes (16)

• Per Cent of Fibro-fatty Component

  at 12-month follow-up

• Event Free Survival

  at 12-month follow-up

• Restenosis Rate

  at 12-month follow-up

• Late Definite Thrombosis

  at 12-month follow-up

• Coronary Vasomotion - Mean Lumen Diameter After Infusion of Acetylcholine 10-6 M

  at 12-month follow-up

Study Arms (3)

Nano group

EXPERIMENTAL

60 patients in Nano group were treated with transplantation of nanoparticles (NP), particularly with a bioengineered patch that was grown with allogenous stem cells pre-cultivated in the medium with NP. After the admission, patients were examined with QCA, and allocated to the trial. The implantation of the patch onto the artery was undergone by the minimally invasive cardiac surgery (MICS CABG) with fixation of the graft to the epicardial myocardium. MICS CABG implies a beating-heart multi-vessel heart surgery performed through several small incisions under direct vision through an anterolateral mini-thoracotomy in the 4th-6th intercostal spaces. The patients can expect high quality of life resuming all everyday activities within a few weeks of their operation. NP were activated with NIR laser at 7 days after the intervention. Patients were treated with bolus of bivalirudin on the day of NP detonation.

Procedure: Transplantation of nanoparticles

Ferro group

ACTIVE COMPARATOR

60 patients in Ferro group were managed with transplantation of iron-bearing nanoparticles (NP), particularly with intracoronary infusion of allogenous stem cells or CD68 targeted micro-bubbles pre-cultivated in the medium with iron-bearing NP. Cells and/ or micro-bubbles were infused with QCA- and IVUS-guidance to the target coronary artery via micro-catheter on the day of admission. The destruction of CD68 targeted micro-bubbles was obtained by using a Sonos 5500 machine with an S3 transducer operating in ultraharmonic mode (transmit, 1.3MHz/ receive, 3.6 MHz) with a mechanical index of 1.5 and a depth of 4 cm. The AXIOM Artis dBC (Siemens) magnetic navigation system was used for precise delivery of NP to the atheroma through two permanent computer-controlled external magnets generating a navigational magnetic field of 0.08 Tesla in any direction. NP were detonated with NIR laser under the protection of anti-platelet therapy.

Procedure: Transplantation of iron-bearing nanoparticles

Stenting control

OTHER

In case of control group (stenting control), XIENCE V stent was implanted to 60 patients. Patients with a single de novo native coronary stenosis of less than 12 mm lesion length, more than 50% stenosis and reference diameter of 3.0 mm as assessed by online QCA were stented by a single stent of 3.0 x 18 mm. The procedure of implantation had to be performed according to common interventional practices including the administration of intracoronary nitroglycerine 0.2 mg of glycerol trinitrate or isosorbide dinitrate and intra-arterial heparin (50-100 U/kg body weight). Predilation with a conventional balloon catheter was recommended before DES deployment according to the manufacturer's recommendation. The protocol recommended the study stent should cover 2 mm of non-diseased tissue on either side of the target lesion. Postdilatation was allowed with a balloon that was shorter than was the study device.

Device: Stenting

Interventions

Transplantation of nanoparticles PROCEDURE

60 patients into nanogroup with the use of 60/15-70/40 nm silica-gold nanoparticles (NPs) transplanted by endoscopic cardiac surgery in the composition of bioengineered on-artery patch grown on the basis of biopolymeric scaffold and host circulating CD45-CD34-CD73+CD105+ progenitor cells

Nano group

Transplantation of iron-bearing nanoparticles PROCEDURE

60 - into ferro-magnetic group with 60/15-70/40 nm silica-gold iron-bearing NPs with delivery in hand of magnetic navigation system

Ferro group

Stenting DEVICE

60 - in sirolimus-eluting stenting control

Also known as: XIENCE V

Stenting control

Eligibility Criteria

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

You may qualify if:

• age 45-65 years old
• male and female
• single- or multi-vessel CAD with flow-limiting lesions
• no indications for coronary artery bypass surgery (CABG)
• stable angina with indications for percutaneous coronary interventions (PCI)
• NYHA (New York Heart Association) I-III functional class of heart failure (HF)
• treated hypertension (in supine position: systole \>140 mm Hg, diastole \>90 mm Hg)
• de novo treated.

You may not qualify if:

• non-compliance,
• angiographic SYNTAX score ≥23
• history of myocardial infarction (MI), unstable angina, PCI or CABG, atrial fibrillation or other dysrhythmias, stroke
• presence of indications for CABG
• presence of contraindications for PCI or CABG
• NYHA IV functional class of HF
• diabetes mellitus (in case of fasting glucose \>7.0 mM/L or random glucose \>11.0 mM/L)
• untreated hypertension
• asthma
• known hypersensitivity or contraindications to anti-platelet drugs
• contrast sensitivity
• participation to any drug- or intervention-investigation during the previous 60 days

Sponsors & Collaborators

• Ural State Medical University: lead
• Ural Institute of Cardiology: collaborator
• De Haar Research Task Force: collaborator
• Ural Federal University: collaborator
• Transfiguration Clinic: collaborator

Study Sites (4)

De Haar Research Task Force

Amsterdam, North Holland, 1069CD, Netherlands

Location

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

Yekaterinburg, Sverdlovsk Oblast, 620000, Russia

Location

Transfiguration Clinic

Yekaterinburg, Sverdlovsk Oblast, 620078, Russia

Location

Ural Institute of Cardiology

Yekaterinburg, Sverdlovsk Oblast, 620144, Russia

Location

Related Publications (7)

• Kharlamov AN, Gabinsky JL. Plasmonic photothermic and stem cell therapy of atherosclerotic plaque as a novel nanotool for angioplasty and artery remodeling. Rejuvenation Res. 2012 Apr;15(2):222-30. doi: 10.1089/rej.2011.1305.

  PMID: 22533437 BACKGROUND

• 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

• Kharlamov AN. Cardiovascular burden and percutaneous interventions in Russian Federation: systematic epidemiological update. Cardiovasc Diagn Ther. 2017 Feb;7(1):60-84. doi: 10.21037/cdt.2016.08.10.

  PMID: 28164014 BACKGROUND

• Kharlamov AN. Glimpse into the Future of Nanotheranostic Strategies for Regression of Atherosclerosis through the Prism of Systems Biomedicine: Systematic Review of Innovations from Multifunctional Nanoformulations to Devices on Chip. Current Nanomedicine 6(3): 186-218, 2016. doi: 10.2174/2468187306666161121142756.

  BACKGROUND

• Kharlamov AN, Zubarev IV, Shishkina EV, Shur VY. Nanoparticles for treatment of atherosclerosis: challenges of plasmonic photothermal therapy in translational studies. Future Cardiol. 2018 Mar;14(2):109-114. doi: 10.2217/fca-2017-0051. Epub 2018 Jan 16. No abstract available.

  PMID: 29336170 BACKGROUND

• Kharlamov AN, Tyurnina AE, Veselova VS, Kovtun OP, Shur VY, Gabinsky JL. Silica-gold nanoparticles for atheroprotective management of plaques: results of the NANOM-FIM trial. Nanoscale. 2015 May 7;7(17):8003-15. doi: 10.1039/c5nr01050k.

  PMID: 25864858 RESULT

• Kharlamov AN, Feinstein JA, Cramer JA, Boothroyd JA, Shishkina EV, Shur V. Plasmonic photothermal therapy of atherosclerosis with nanoparticles: long-term outcomes and safety in NANOM-FIM trial. Future Cardiol. 2017 Jul;13(4):345-363. doi: 10.2217/fca-2017-0009. Epub 2017 Jun 23.

  PMID: 28644056 RESULT

Related Links

• Ural Institute of Cardiology
• Ural State Medical University
• Ural Center of Modern Nanotechnologies, Institute of Natural Sciences, Ural Federal University
• Transfiguration Clinic
• De Haar Research Task Force

MeSH Terms

Conditions

Angina, Stable; Heart Failure; Atherosclerosis

Interventions

Stents

Condition Hierarchy (Ancestors)

Angina Pectoris; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Chest Pain; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Arteriosclerosis; Arterial Occlusive Diseases

Intervention Hierarchy (Ancestors)

Prostheses and Implants; Equipment and Supplies

Limitations and Caveats

The study was launched as a PROBE trial. But randomization was broken because of the specific study design, where procedures differ significantly, and impossibility to calculate sample size due to absolute novelty of the technology.

Results Point of Contact

• Title: Dr. Alexander Kharlamov
• Organization: Ural Institute of Cardiology

drskharlamov@gmail.com

0031627849118

Study Officials

• Jan Gabinsky, MD, PhD, DSc

  Ural Institute of Cardiology

  STUDY DIRECTOR

• Olga Kovtun, MD, PhD

  Ural State Medical University

  STUDY CHAIR

• Alexander Kharlamov, M.D., FESC, FACC, FEACVI

  De Haar Research Task Force

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• 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: December 30, 2010
• First Posted: January 5, 2011
• Study Start: April 1, 2007
• Primary Completion: April 1, 2009
• Study Completion: August 1, 2016
• Last Updated: March 17, 2021
• Results First Posted: August 30, 2012

Record last verified: 2021-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: The data-sets will be provided in Mendeley and ResearchGate being accompanied to the published articles in 2013-2020.
• Access Criteria: There are no specific criteria, but the access to the raw data is partly restricted by the Russian Federal Security Service for indefinite time.

Locations

RU (3); NL (1)