Ignite Creation Date:
2024-05-05 @ 11:10 PM
Last Modification Date:
2024-10-26 @ 10:29 AM
Study NCT ID:
NCT01270139
Status:
COMPLETED
Last Update Posted:
2021-03-17
First Post:
2010-12-30
Brief Title:
Plasmonic Nanophotothermal Therapy of Atherosclerosis
Sponsor:
Ural State Medical University
Organization:
Ural State Medical University
Study Overview
Official Title:
Plasmonic Photothermal Therapy of Flow-Limiting Atherosclerotic Lesions With Silica-Gold Nanoparticles a First-in-Man Study
Status:
COMPLETED
Status Verified Date:
2021-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
NANOM-FIM
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 n180 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 111 ratio to receive either 1 nano-intervention with delivery of silica-gold NP in mini-surgery implanted bioengineered on-artery patch n60 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 n60 versus 3 stent implantation n60 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 n13 Subjects in the second subset were undergone drug-coated balloon pre-dilation with further nano-technique n20 Lesions in patients of the third subset were not prepared for the nano-approach n147 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
The completed in July 2012 interventional three arms n180 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 111 ratio to receive either 1 nano-intervention with delivery of silica-gold NP in mini-surgery implanted bioengineered on-artery patch n60 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 n60 versus 3 stent implantation n60 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 n13 Subjects in the second subset were undergone drug-coated balloon pre-dilation with further nano-technique n20 Lesions in patients of the third subset were not prepared for the nano-approach n147 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
Detailed Description:
Cardiovascular disease CVD is one of the main cause of disability and death worldwide The underlying cause generally is atherosclerosis and more in particular thrombotic rupture of an atherosclerotic plaque in a vital artery The restoration of blood flow to ischemic myocardium is established as the preeminent objective for the treatment of patients with CVD Some modern angioplasty techniques generally just manipulate the form of the plaque and have some clinical and technical restrictions relatively high complication rate and restenosis risk
The most common techniques in current practice are angioplasty with stenting and CABG surgery for patients with multivessel disease Balloon angioplasty and stenting in fact manage the form of the plaque and does not create a significant problem of plaque residue flowing from the site Once a role for elective stent implantation was established the next goal was to overcome the complications of subacute stent thrombosis first of all with the use of drug-eluting stents and neointimal hyperplasia bare-metal stents through pharmacologic and physical means Among unresolved issues the investigators can describe restrictions in patients with stenosis of an unprotected left main coronary artery multivessel disease diabetes mellitus still rather high rate of in-stent restenosis and as a solution of the problem with a foreign body in a vessel the development of biodegradable stents Among physical obstacles for stenting the investigators may note that atherosclerotic plaque build-up can exist in a number of different forms The plaque can be quite hard and scaly or more fatty and pliable Moreover Dr Peters D with colleagues from Santa-Barbara 2009 published own data about new modular multifunctional micelles that contain a targeting element a fluorophore and when desired a drug component in the same particle Targeting atherosclerotic plaques in ApoE-KO mice fed a high-fat diet was accomplished with the pentapeptide cysteine-arginine-glutamic acid-lysine-alanine which binds to clotted plasma proteins The fluorescent micelles bind to the entire surface of the plaque and notably concentrate at the shoulders of the plaque a location that is prone to rupture They also show that the targeted micelles deliver an increased concentration of the anticoagulant drug hirulog to the plaque compared with untargeted micelles that may reduce bleeding complications and atherogenesis
Moreover the ability of statin drugs to reduce the volume of atherosclerotic plaque in the coronary artery wall termed plaque regression has received much attention The statins have a remarkable track record of lowering cholesterol and improving survival Apart from lowering low-density lipoprotein cholesterol LDL-C levels they also have a multitude of other actions often collectively described as pleiotropic effects JUPITER 2003 REVERSAL 2004 PROVE IT 2004 ESTABLISH 2004 and ASTEROID 2006 trials have shown that low LDL levels after intensive statin therapy when accompanied by raised HDL can regress or partially reverse the plaque buildup in the coronary arteries The findings suggest that the various components of atheroma respond differently to treatment with medical therapies and can be used to target plaques that are likely to respond Thus lipid pool inflammatory reaction in the forms of cellular migration humoral substance release and oedema are still the most likely to be targets of pharmacotherapy But for instance fibrous tissue mineral deposits and ground substance would seem to be irreversible despite metabolic manipulation
Numerous devices recently have been described that utilize the application of heat to resolve atherosclerotic plaque laser technique electrosurgical removing of plaque or with the use of radio frequency sparking and others Plasmonics is a novel invasive approach in medicine and metal nanoparticles are a new type of optically active composite spherical one consisting of a dielectric core covered by a thin metallic shell which is typically gold When nanoparticles are irradiated with a near-infrared laser they absorb energy which is quickly transferred through nonradiative relaxation into heat and accompanying effects and eventually leads to irreparable damage of tissue In oncology metal nanoparticles may provide a novel means of targeted plasmonic photothermal therapy PPTT in tumour tissue minimizing damage to surrounding healthy tissue However this approach does not use in cardiology today possessing the great potential for angioplasty The efficiency of nanotechnologies however is limited by gaps in the current understanding of the thermal interactions between nanoparticles and laser light pulses or continuous waves in the context of complex biological environments Irradiation even with moderate pulses of energy can induce melting evaporation and fragmentation of nanoparticles These events can drastically alter the intended therapeutic effects and lead to the formation of vapour bubbles as well as acoustic waves and shock waves But the last disadvantages can become advantages depending on the purposes of the treatment Thus the study opens a new chapter in the history of plasmonics
The investigators designed this study to check potent clinical opportunities efficacy and safety of such a novel technique for angioplasty as plasmonic atherodestruction The investigators have drawn the following research questions 1 Is it possible to plasmonically entirely destruct a plaque with minimal complications 2 What level of safety is typical for the different approaches if compare with stenting 3 What are the advantages and disadvantages of the different delivery techniques - stem cells or magnetic field 4 What is the meaning of the transplanted mesenchymal CD73CD105 stem-progenitor cells for atherosclerosis management 5 Can plasmonic nanophotothermal therapy PPTT get an alternative to stenting
Plasmonic photothermal therapy PPTT can potentially reduce the volume of plaque PPTT melts an atherosclerotic plaque tissue with irreparable burning of targeted tissues vapour bubbling of cellular cytoplasm and extracellular matrix with subsequent degradation of tissues and destructive effects of acoustic and shock waves as the possible plaque-killing mechanisms NPs are absolutely safe for an organism but entire kinetics is mostly unknown The most dangerous approach with the lowest level of efficacy and safety is delivery of NPs with microbubbles if compare with stem cell-based one Mesenchymal stem cells have appropriate effectiveness as a local delivery system with a lot of beneficial properties such as anti-inflammatory anti-apoptotic and multi-metabolic effects leading to plaque degradation Thus PPTT can become an alternative to stenting
Among potential problems the investigators may name 1 technique of the delivery of these nanoparticles directly into the plaque stem cells aleuronic microbubbles with surfaced antibodies as a local delivery system direct injection or infusion into the coronary arteries and plaques during CABG or PCI 2 high risk of acute fatal atherothrombosis at the heat site due to destruction of the fibrous cap of plaque role of nanoparticles adhesion on the surface of endothelium 3 long-term effects of the nanodestruction locally and in entire organism distribution and effects of accumulation in different organs 4 mechanism of this effect plasmonic microexplosion and burning of tissue lysis of cells due to vapor bubbling of cellular cytoplasm and extracellular tissues destructive acoustic and shock waves 5 optimal biophysical parameters and necessary energy levels of nanodetonation to prevent burning of surrounding tissues and perforation of the vessel 6 plasmonic damage is irreparable and it means the investigators have to combine it with another biotechnology for the restoration of vessel such as the use of stem cells 7 optimal type of stem cells source origin level of differentiation potential properties
So disadvantages of current low-invasive approaches stenting statin drugs and others laser electrosurgery devices
Foreign body in the heart
Restenosis including neointimal hyperplasia adventitial and circulating stem-progenitor cells of different origin are involved
Risk of fatal acute or sub-acute atherothrombosis including in-stent sub-acute atherothrombosis
Non-pathogenetic - cannot reverse or significantly regress the plaque
No effect for remodeling and calcification restriction for necessary remodeling
Clinical restrictions for some group multivessel disease left main CAD diabetes mellitus severe CAD and etc on another hand CABG is a very traumatic procedure solution - MICS including achievements in endoscopic stereotaxic surgery but CABG is still an approach in charge in severe or high-risk patients
Disadvantages of the studied approach
The necessity of the special delivery technique
The lost function of the artery - irreparable pro-fibrotic damage - the necessity of another clinical management for restoration of tissue - the necessity of the restoration therapy with stem cells
The threat of acute fatal atherothrombosis due to rupture of vulnerable plaque
Cannot treat non-organic part of plaque - the necessity of the special therapy - stem cells
The harm of potent detrimental side-effects - vapour bubbling boiling of cytoplasm and ECM with subsequent lysis of cells and provocation of pro-apoptotic cascades acoustic and shock waves due to the plasma-generated laser-related detonation of nanoshells in tissue
Erratic uncontrollable heating - surrounding tissue of the site of interest can achieve a temperature until 38-39 But at the site of burning final temperature can be at about 50-180 C cauterization searing melting effect with following the pro-fibrous effect of tissue
The most common techniques in current practice are angioplasty with stenting and CABG surgery for patients with multivessel disease Balloon angioplasty and stenting in fact manage the form of the plaque and does not create a significant problem of plaque residue flowing from the site Once a role for elective stent implantation was established the next goal was to overcome the complications of subacute stent thrombosis first of all with the use of drug-eluting stents and neointimal hyperplasia bare-metal stents through pharmacologic and physical means Among unresolved issues the investigators can describe restrictions in patients with stenosis of an unprotected left main coronary artery multivessel disease diabetes mellitus still rather high rate of in-stent restenosis and as a solution of the problem with a foreign body in a vessel the development of biodegradable stents Among physical obstacles for stenting the investigators may note that atherosclerotic plaque build-up can exist in a number of different forms The plaque can be quite hard and scaly or more fatty and pliable Moreover Dr Peters D with colleagues from Santa-Barbara 2009 published own data about new modular multifunctional micelles that contain a targeting element a fluorophore and when desired a drug component in the same particle Targeting atherosclerotic plaques in ApoE-KO mice fed a high-fat diet was accomplished with the pentapeptide cysteine-arginine-glutamic acid-lysine-alanine which binds to clotted plasma proteins The fluorescent micelles bind to the entire surface of the plaque and notably concentrate at the shoulders of the plaque a location that is prone to rupture They also show that the targeted micelles deliver an increased concentration of the anticoagulant drug hirulog to the plaque compared with untargeted micelles that may reduce bleeding complications and atherogenesis
Moreover the ability of statin drugs to reduce the volume of atherosclerotic plaque in the coronary artery wall termed plaque regression has received much attention The statins have a remarkable track record of lowering cholesterol and improving survival Apart from lowering low-density lipoprotein cholesterol LDL-C levels they also have a multitude of other actions often collectively described as pleiotropic effects JUPITER 2003 REVERSAL 2004 PROVE IT 2004 ESTABLISH 2004 and ASTEROID 2006 trials have shown that low LDL levels after intensive statin therapy when accompanied by raised HDL can regress or partially reverse the plaque buildup in the coronary arteries The findings suggest that the various components of atheroma respond differently to treatment with medical therapies and can be used to target plaques that are likely to respond Thus lipid pool inflammatory reaction in the forms of cellular migration humoral substance release and oedema are still the most likely to be targets of pharmacotherapy But for instance fibrous tissue mineral deposits and ground substance would seem to be irreversible despite metabolic manipulation
Numerous devices recently have been described that utilize the application of heat to resolve atherosclerotic plaque laser technique electrosurgical removing of plaque or with the use of radio frequency sparking and others Plasmonics is a novel invasive approach in medicine and metal nanoparticles are a new type of optically active composite spherical one consisting of a dielectric core covered by a thin metallic shell which is typically gold When nanoparticles are irradiated with a near-infrared laser they absorb energy which is quickly transferred through nonradiative relaxation into heat and accompanying effects and eventually leads to irreparable damage of tissue In oncology metal nanoparticles may provide a novel means of targeted plasmonic photothermal therapy PPTT in tumour tissue minimizing damage to surrounding healthy tissue However this approach does not use in cardiology today possessing the great potential for angioplasty The efficiency of nanotechnologies however is limited by gaps in the current understanding of the thermal interactions between nanoparticles and laser light pulses or continuous waves in the context of complex biological environments Irradiation even with moderate pulses of energy can induce melting evaporation and fragmentation of nanoparticles These events can drastically alter the intended therapeutic effects and lead to the formation of vapour bubbles as well as acoustic waves and shock waves But the last disadvantages can become advantages depending on the purposes of the treatment Thus the study opens a new chapter in the history of plasmonics
The investigators designed this study to check potent clinical opportunities efficacy and safety of such a novel technique for angioplasty as plasmonic atherodestruction The investigators have drawn the following research questions 1 Is it possible to plasmonically entirely destruct a plaque with minimal complications 2 What level of safety is typical for the different approaches if compare with stenting 3 What are the advantages and disadvantages of the different delivery techniques - stem cells or magnetic field 4 What is the meaning of the transplanted mesenchymal CD73CD105 stem-progenitor cells for atherosclerosis management 5 Can plasmonic nanophotothermal therapy PPTT get an alternative to stenting
Plasmonic photothermal therapy PPTT can potentially reduce the volume of plaque PPTT melts an atherosclerotic plaque tissue with irreparable burning of targeted tissues vapour bubbling of cellular cytoplasm and extracellular matrix with subsequent degradation of tissues and destructive effects of acoustic and shock waves as the possible plaque-killing mechanisms NPs are absolutely safe for an organism but entire kinetics is mostly unknown The most dangerous approach with the lowest level of efficacy and safety is delivery of NPs with microbubbles if compare with stem cell-based one Mesenchymal stem cells have appropriate effectiveness as a local delivery system with a lot of beneficial properties such as anti-inflammatory anti-apoptotic and multi-metabolic effects leading to plaque degradation Thus PPTT can become an alternative to stenting
Among potential problems the investigators may name 1 technique of the delivery of these nanoparticles directly into the plaque stem cells aleuronic microbubbles with surfaced antibodies as a local delivery system direct injection or infusion into the coronary arteries and plaques during CABG or PCI 2 high risk of acute fatal atherothrombosis at the heat site due to destruction of the fibrous cap of plaque role of nanoparticles adhesion on the surface of endothelium 3 long-term effects of the nanodestruction locally and in entire organism distribution and effects of accumulation in different organs 4 mechanism of this effect plasmonic microexplosion and burning of tissue lysis of cells due to vapor bubbling of cellular cytoplasm and extracellular tissues destructive acoustic and shock waves 5 optimal biophysical parameters and necessary energy levels of nanodetonation to prevent burning of surrounding tissues and perforation of the vessel 6 plasmonic damage is irreparable and it means the investigators have to combine it with another biotechnology for the restoration of vessel such as the use of stem cells 7 optimal type of stem cells source origin level of differentiation potential properties
So disadvantages of current low-invasive approaches stenting statin drugs and others laser electrosurgery devices
Foreign body in the heart
Restenosis including neointimal hyperplasia adventitial and circulating stem-progenitor cells of different origin are involved
Risk of fatal acute or sub-acute atherothrombosis including in-stent sub-acute atherothrombosis
Non-pathogenetic - cannot reverse or significantly regress the plaque
No effect for remodeling and calcification restriction for necessary remodeling
Clinical restrictions for some group multivessel disease left main CAD diabetes mellitus severe CAD and etc on another hand CABG is a very traumatic procedure solution - MICS including achievements in endoscopic stereotaxic surgery but CABG is still an approach in charge in severe or high-risk patients
Disadvantages of the studied approach
The necessity of the special delivery technique
The lost function of the artery - irreparable pro-fibrotic damage - the necessity of another clinical management for restoration of tissue - the necessity of the restoration therapy with stem cells
The threat of acute fatal atherothrombosis due to rupture of vulnerable plaque
Cannot treat non-organic part of plaque - the necessity of the special therapy - stem cells
The harm of potent detrimental side-effects - vapour bubbling boiling of cytoplasm and ECM with subsequent lysis of cells and provocation of pro-apoptotic cascades acoustic and shock waves due to the plasma-generated laser-related detonation of nanoshells in tissue
Erratic uncontrollable heating - surrounding tissue of the site of interest can achieve a temperature until 38-39 But at the site of burning final temperature can be at about 50-180 C cauterization searing melting effect with following the pro-fibrous effect of tissue
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None