Plasmonic Nanophotothermic Therapy of Atherosclerosis (NANOM FIM)

This study has been completed.
Sponsor:
Collaborator:
Ural Institute of Cardiology
Information provided by (Responsible Party):
Alexandr Kharlamov, Ural State Medical Academy
ClinicalTrials.gov Identifier:
NCT01270139
First received: December 30, 2010
Last updated: August 30, 2012
Last verified: August 2012
  Purpose

The investigators hypothesize that nanoburning is very challenging technique to demolish and reverse the plaque especially in combination with stem cell technologies promising functional restoration of the vessel wall.

Prevention of atherosclerosis and treatment of its complications remain a clinical challenge. The reversal of atherogenesis becomes a new more attractive target for the progress of cardiovascular therapy, and coronary device development.

HMGCoA reductase inhibitors have an outstanding track record of lowering cholesterol and improving outcomes. Some clinical trials have demonstrated that lowering LDL levels through intensive statin therapy while accompanied by raised HDL, can slow progression, or even partially reduce the total atheroma volume (up to 6.38 mm3) in coronary arteries. Of note, plaque regression was associated only with a 30% relative reduction in events. By way of comparison, recombinant ApoA-I Milano demonstrated a 14.1 mm3 reduction in total atheroma volume31. These findings suggest that fibrous tissue and mineral deposits may resist risk factor modification or systemic drug therapy.

Numerous devices utilizing heat and high-energy light such as laser technology (excimer ultra-violet laser), electrosurgical approach, radio frequency sparking have been recently described as the applications to treat atheroma. Plasmonic photothermal therapy (PPTT) is the novel invasive approach in cardiology, and noble-metal nanoparticles are a new type of optically active composite spherical particles on the nanoscale. When such nanoparticles are irradiated with near-infrared (NIR) laser, they absorb energy, which is quickly transferred through non-radiative relaxation into heat and accompanied effects, and eventually leads to irreparable damage of any tissue, for instance of atheroma. Our previous bench studies PLASMONICS24 documented acceptable level of safety and significant efficacy of PPTT with unprecedented plaque burden reduction up to 79.4 mm3.

The completed first-in-man trial (the NANOM FIM trial) assessed the safety and feasibility of two delivery techniques for NP, and PPTT of atherosclerotic lesions in patients with coronary artery disease (CAD) and SYNTAX score that equals or less than 22. In addition, using an implantation of everolimus-eluting stent (EES; Abbott Vascular, Santa Clara, CA, USA) as a control group, we compared the main options of safety and efficacy of the tested nanotechnologies and well-known XIENCE V stent.

The completed observational 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 photothermic therapy (PPTT) of atherosclerotic lesions. Patients were randomly 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 mean TAV reduction at 12 months in Nano group was 60.3 mm3 (SD 39.5; min 41.9 mm3, max 94.2 mm3; p<0.05). The reduction of the PAV (per cent atheroma volume) post-procedure/ at 12-month follow-up was 12.6/44.8%, 13.1/ 43.2%, 20.2/ 22.7% (p<0.05) in groups respectively. The increase of minimal lumen diameter from baseline to post-procedure/ at 12-month follow-up was 5.9/ 63.6%, 21.2/ 63.8%, 56.2/ 62.4% (p<0.05) 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 others (91.7% vs 81.7% and 80% respectively; p<0.05).

Atherodestruction in hands of plasmonic resonance of the silica-gold NP resulted in significant regression of coronary atherosclerosis. Both approaches for delivery of NP have acceptable for clinical practice level of safety as well as similar degree of regression of TAV. (This project was not funded in any part by a commercial organization.)


Condition Intervention Phase
Stable Angina
Heart Failure
Atherosclerosis
Multivessel Coronary Artery Disease
Procedure: Transplantation of nanoparticles
Procedure: Transplantation of iron-bearing nanoparticles
Device: Put in stenting
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Plasmonic Photothermal Therapy of Flow-Limiting Atherosclerotic Lesions With Silica-Gold Nanoparticles: a First-in-Man Study

Resource links provided by NLM:


Further study details as provided by Ural State Medical Academy:

Primary Outcome Measures:
  • Total Atheroma Volume [ Time Frame: at 12-month follow-up ] [ Designated as safety issue: No ]
    Total atheroma volume (TAV, plaque-media volume, mm3) at 12 months. Quantative 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.


Secondary Outcome Measures:
  • Per Cent of Fibro-fatty Component [ Time Frame: at 12-month follow-up ] [ Designated as safety issue: No ]
    IVUS (intravascular ultrasound) and IVUS-VH (virtual histology) images were acquired simultaneously with a phased array 20 MHz intravascular ultrasound catheter EagleEye (Volcano Co., Rancho Cordova, CA, USA) with motorized pull-back at a constant speed of 0.5 mm/s. Four tissue components (necrotic core - red; dense calcium - white; fibrous - green; and fibro-fatty - light green or yellow) were identified with autoregressive classification systems. For each cross section stent struts were detected as areas of apparent dense calcium and necrotic core. All IVUS analysis was performed offline by a CoreLab of the Ural Institute of Cardiology.

  • Event Free Survival [ Time Frame: at 12-month follow-up ] [ Designated as safety issue: Yes ]
    The Kaplan-Meier analysis of the cardiac event-free survival (failure-free survival). The end point in this study was cardiac event-free survival during follow-up, starting at randomization. Cardiac events included cardiac death, myocardial infarction and unintended revascularization. Cardiac death was defined as sudden death, death after the onset of symptoms suggestive of cardiac ischemia and death due to heart failure. Noncardiac death was defined as death due to all other causes. Myocardial infarction was defined as an increase in cardiac enzymes or new pathologic Q-waves on the ECG, or both. Unintended revascularization was defined as PTCA or CABG performed due to worsening of the patient's clinical condition, rather than the PTCA or CABG assigned by the revascularization team when patient management was determined.

  • Restenosis Rate [ Time Frame: at 12-month follow-up ] [ Designated as safety issue: Yes ]
    Restenosis (stenosis>50%) rate

  • Late Definite Thrombosis [ Time Frame: at 12-month follow-up ] [ Designated as safety issue: Yes ]
    Late definite thrombosis rate

  • Coronary Vasomotion - Mean Lumen Diameter After Infusion of Acetylcholine 10-6 M [ Time Frame: at 12-month follow-up ] [ Designated as safety issue: No ]
    Coronary vasomotion was assessed with QCA. End-diastolic images of coronary arteries were evaluated at baseline, after intravascular infusion of acetylcholine (through a microcatheter at increasing doses up to 10-8, 10-7, 10-6 M with a washout period of at least five minutes between each dose), and after nitroglycerine application following acetylcholine (100 µg orally). In all patients, measurements were performed in two segments on site of intervention while 960 seconds. The artery diameter was calibrated against the contrast-filled tip of the catheter. Vasoconstriction to acetylcholine was defined as a 3% change of the mean lumen diameter after infusion of the maximal dose of acetylcholine. An investigator blinded to treatment group performed all measurements.

  • Per Cent Atheroma Volume [ Time Frame: at 12-month follow-up ] [ Designated as safety issue: No ]
    Per cent atheroma volume (PAV, plaque burden, %). Quantative 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.

  • Target Lesion Revascularization [ Time Frame: at 12-month follow-up ] [ Designated as safety issue: Yes ]
    Target lesion revascularization, per cent

  • Per Cent of Fibrous Component [ Time Frame: at 12-month follow-up ] [ Designated as safety issue: No ]
    IVUS (intravascular ultrasound) and IVUS-VH (virtual histology) images were acquired simultaneously with a phased array 20 MHz intravascular ultrasound catheter EagleEye (Volcano Co., Rancho Cordova, CA, USA) with motorized pull-back at a constant speed of 0.5 mm/s. Four tissue components (necrotic core - red; dense calcium - white; fibrous - green; and fibro-fatty - light green or yellow) were identified with autoregressive classification systems. For each cross section stent struts were detected as areas of apparent dense calcium and necrotic core. All IVUS analysis was performed offline by a CoreLab of the Ural Institute of Cardiology.

  • Per Cent of Necrotic Core [ Time Frame: at 12-month follow-up ] [ Designated as safety issue: No ]
    IVUS (intravascular ultrasound) and IVUS-VH (virtual histology) images were acquired simultaneously with a phased array 20 MHz intravascular ultrasound catheter EagleEye (Volcano Co., Rancho Cordova, CA, USA) with motorized pull-back at a constant speed of 0.5 mm/s. Four tissue components (necrotic core - red; dense calcium - white; fibrous - green; and fibro-fatty - light green or yellow) were identified with autoregressive classification systems. For each cross section stent struts were detected as areas of apparent dense calcium and necrotic core. All IVUS analysis was performed offline by a CoreLab of the Ural Institute of Cardiology.

  • Per Cent of Calcium [ Time Frame: at 12-month follow-up ] [ Designated as safety issue: No ]
    IVUS (intravascular ultrasound) and IVUS-VH (virtual histology) images were acquired simultaneously with a phased array 20 MHz intravascular ultrasound catheter EagleEye (Volcano Co., Rancho Cordova, CA, USA) with motorized pull-back at a constant speed of 0.5 mm/s. Four tissue components (necrotic core - red; dense calcium - white; fibrous - green; and fibro-fatty - light green or yellow) were identified with autoregressive classification systems. For each cross section stent struts were detected as areas of apparent dense calcium and necrotic core. All IVUS analysis was performed offline by a CoreLab of the Ural Institute of Cardiology.

  • Minimal Lumen Diameter [ Time Frame: at 12-month follow-up ] [ Designated as safety issue: No ]
    Minimal lumen diameter (MLD, mm)


Enrollment: 180
Study Start Date: April 2007
Study Completion Date: June 2012
Primary Completion Date: April 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Nano group
60 patients in Nano group were treated with bioengineered patch that was grown with allogenious 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 aterolateral mini-thoracotomy in the 4th-6th intercostal spaces. The approach considered as an alternative to PCI allowing quick recover without major complications. 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
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
Active Comparator: Ferro group
60 patients in Ferro group were managed with intracoronary infusion of allogenious 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 at the Acute Care Unit. 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 with opportunity to produce a spot at the area of target artery and lesion. NP were detonated with NIR laser at the end of the procedure under the protection of anti-platelet therapy.
Procedure: Transplantation of iron-bearing nanoparticles
60 - into ferro-magnetic group with 60/15-70/40 nm silica-gold iron-bearing NPs with delivery in hand of magnetic navigation system
Stenting control
In case of control group, 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: Put in stenting
60 - in sirolimus-eluting stenting control
Other Name: XIENCE V

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   45 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • non-compliance,
  • angiographic SYNTAX score ≥23
  • history of myocardial infarction (MI), unstable angina, PCI or CABG, atrial fibrillation or other disrhythmias, 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01270139

Locations
Russian Federation
Ural Institute of Cardiology
Yekaterinburg, Sverdlovsk oblast, Russian Federation, 620144
Sponsors and Collaborators
Ural State Medical Academy
Ural Institute of Cardiology
Investigators
Study Director: Jan Gabinsky, M.D., Ph.D. Ural Institute of Cardiology
Study Chair: Olga Kovtun, M.D., Ph.D. Ural State Medical Academy
Principal Investigator: Alexander Kharlamov, M.D. Ural Institute of Cardiology
  More Information

Additional Information:
No publications provided

Responsible Party: Alexandr Kharlamov, Research manager, Ural State Medical Academy
ClinicalTrials.gov Identifier: NCT01270139     History of Changes
Other Study ID Numbers: NANOM FIM
Study First Received: December 30, 2010
Results First Received: July 26, 2012
Last Updated: August 30, 2012
Health Authority: Russia: Ethics Committee

Keywords provided by Ural State Medical Academy:
nanoparticles
mesenchymal stem cell
plasmonics
atherosclerosis
IVUS
stenting

Additional relevant MeSH terms:
Heart Failure
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Atherosclerosis
Arteriosclerosis
Angina, Stable
Heart Diseases
Cardiovascular Diseases
Arterial Occlusive Diseases
Vascular Diseases
Angina Pectoris
Chest Pain
Pain
Signs and Symptoms

ClinicalTrials.gov processed this record on October 19, 2014