Evaluation of HealinG of Polymer-Free Biomlimus A9-Coated Stent by Optical Coherence Tomography (EGO-BIOFREEDOM)

Study Overview
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Brief Summary
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Since polymers have been identified as a possible cause of late complications of drug eluting stents, new stents are being designed to improve polymers' biocompatibility or to bond drugs on stents without polymers. Biolimus A9 is the therapeutic agent used in the BioFreedom drug coated stent. Biolimus A9 is a proprietary semi-synthetic sirolimus derivative. It is highly lipophilic, rapidly absorbed in tissues, and able to reversibly inhibit growth factor-stimulated cell proliferation. In this study, we use intracoronary optical coherence tomography (OCT) to evaluate the BioFreedom Stents after implantation regarding endovascular healing over time as primary objective; and also to evaluate secondary OCT, angiographic and clinical outcomes at various specific time points.

Detailed Description
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Intra-coronary stenting is currently the standard of care post-balloon angioplasty for ischemic heart disease. Traditionally, bare metal stent (BMS) is used but in recent years it has been largely been replaced by drug-eluting stent (DES) which has reduced rates of restenosis. (1) However, the long term safety of DES still remains controversial due to reports of late stent thrombosis which presumably occurs secondary to delayed arterial healing and local hypersensitivity reactions which may be related to the drug, the polymer, or both. (2). Virmani et al (3) reported that patients who died of late stent thrombosis 18 months after sirolimus-eluting stent (SES) implantation showed a severe localized hypersensitivity reaction that involved the whole vessel wall and this reaction may be caused by polymer or from the drug-release kinetics of SES. It is known from preclinical and clinical studies that, nonabsorbable polymer can induce persistent inflammation which may lead to delayed cellular proliferation and 'late catch-up' restenosis (4). Early (ie first) generation DES consisted of a metal stent for vessel scaffolding, cytotoxic drug for neointimal growth inhibition and a polymer coating to improve the biocompatibility of the stents or as a vehicle to load drugs onto stents. Since polymers have been identified as a possible cause of late complications of DES, new stents are being designed to improve polymers' biocompatibility or to bond drugs on stents without polymers. Biodegradable polymers are likely to be safer than nonabsorbable polymers because inflammation will be eliminated after the polymer degrades. The BioFreedom drug coated stent (DCS) Coronary Stent Delivery System is comprised of three key components including 1) a 316 L stainless steel bare metal stent platform which has been modified with a proprietary surface treatment resulting in a selectively micro-structured, abluminal surface. The selectively micro-structured surface allows 2) Biolimus A9TM (drug) adhesion to the abluminal surface of the stent without the use of a polymer or binder. The drug-coated stent is crimped onto 3) a delivery system which includes a high pressure, semi-compliant balloon incorporated onto the distal tip of a rapid exchange delivery catheter system. The delivery system has two radiopaque markers inside the balloon, which fluoroscopically mark the ends of the stent to facilitate proper stent placement. Biolimus A9 is the therapeutic agent used in the BioFreedom DCS. Biolimus A9 is a proprietary semi-synthetic sirolimus derivative. It is highly lipophilic, rapidly absorbed in tissues, and able to reversibly inhibit growth factor-stimulated cell proliferation. Current data suggest that Biolimus A9, on a molecular level, forms a complex with the cytoplasmic proteins that inhibit the cell cycle between the G0 and G1 phase. The result is an interruption of the cascade governing cell reproduction, growth, and proliferation. Related pharmaceuticals, sirolimus and everolimus, are well tolerated cytostatic immunosuppressive agents with predictable and similar adverse event profiles. Biolimus A9 is closely related chemically to both sirolimus and everolimus. Based on administration in healthy volunteers, Biolimus A9 has been shown to have a very similar adverse event profile to these other two drugs when used at equivalent dose levels., Biolimus A9 easily crosses the cell membrane to achieve therapeutic effects in target smooth muscle cells and, compared with the sirolimus-eluting Cypher stent (SES), the high lipophilicity of BA9 leads to relatively low systemic exposure.(5) Furthermore, the drug coating is applied only to the abluminal surface of the stent, allowing the drug release to be directed almost entirely into the vessel wall where it targets the smooth muscle cells injured by the angioplasty procedure. On the other hand, there is little drug release on the luminal surfaces of the stent, thus there is less inhibition of endothelial cells which need to grow on the inside of the stent in order for healing to occur. Animal studies have shown the Biofreedom stent demonstrates equivalent or less early and late reduction of intimal smooth muscle cell proliferation compared with the Cypher Sirolimus-eluting stent (SES) in a porcine model. After implantation of BioFreedom stent, delayed arterial healing has been shown to be minimal, and there was no increased inflammation at 180 days compared with SES implantation (6). Pharmacokinetic and tissue concentration analyses showed that there was no high early peaking of Biolimus A9 level in blood (6). On-going studies of Biofreedom in humans showed non-inferiority of in-stent late lumen loss at 12 months versus paclitaxel eluting stents (PES) (7). This current EGO BIOFREEDOM study protocol is designed based on the approved protocols of the EGO Study and EGO-COMBO Study, which were both successfully completed. We aim to focus mainly on the time frame, degree of endothelialization, and the subsequent neointimal proliferation after BioFreedom stent implantation, as assessed by the state-of-the-art intracoronary imaging - optical coherence tomography (OCT), which has been used extensively in the completed EGO and EGO-COMBO study. Indeed, intracoronary optical coherence tomography (OCT) is a simple catheter-based imaging technique using optic fibre to achieve very detailed assessment (resolution down to 100 microns) in intra-coronary stent apposition, early stent coverage (endothelialization) and late stent neoinitmal growth (restenosis). It is performed as part of routine cardiac catheterization procedure and provides high-resolution cross sectional images of the coronary arteries. OCT has been shown to be safe in clinical practice (8). The LightLab C7XR OCT system (Frequency Domain OCT) is a commercial available product with CE Mark and FDA approval, which has been used in the EGO Studies. The OCT catheter is a non-occlusive optic fibre which is extremely small and flexible. It poses no additional risk to the patient other than those inherent risks of a standard angioplasty procedure.

Official Title
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Evaluation of Healing the Biofreedom Stent Study

Conditions
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Coronary Disease

Intervention / Treatment
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* Device: coronary intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient aged 18-85 years old Patient indicated for percutaneous coronary intervention with coronary artery disease and without contraindications to implantation of drug eluting stents Patient who agrees to have follow-up coronary angiograms Exclusion Criteria: Patient who refuses to consent to multiple coronary angiograms or coronary angioplasty

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Biofreedom stent<br>Coronary intervention | Device: coronary intervention<br>* The BioFreedom drug coated stent (DCS) Coronary Stent Delivery System is comprised of three key components<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OCT Findings on Coverage (Degree of Endothelialisation/Coverage) From 1 to 9 Months. | The percentage of strut coverage and category of coverage (A to F) from 1 month to 9 months by longitudinal sequential OCT assessments. A. Definitely uncovered - strut not covered by tissue, and both sides appear square; B. Uncovered with abnormal in-stent tissue - strut covered by irregular tissue or fibrin, and both sides appear square; C. Partially uncovered - strut partially covered by tissue but only one side has a smooth continuous shoulder; D. Covered (protruding) - strut covered by thin continuous tissue on both sides but still extending into the lumen; E. Covered (embedded) - strut covered by continuous tissue or neointima and not interrupting the smooth lumen contour; F. Covered (proliferative) - strut covered with excessive growth of neointima with thickness >0.3 mm. | 1 to 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OCT Endpoints (Neointimal Metrics), QCA Endpoints (Late Lumen Loss at 9 Months), and Clinical Endpoints (MACE at 9 Months and 12 Months). A Subgroup Analysis Would be Performed for Diabetic Patients. | Secondary endpoints would consist of OCT endpoints (neointimal area, neointimal thickness, neointimal volume, and percentage neointimal volume ), QCA endpoints (late lumen loss at 9 months), and clinical endpoints (MACE, including stent thrombosis up to 12 months). A subgroup analysis will be performed for DM patients. | 9 months and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Optical Coherence Tomography, Biofreedom Stent