Study of BioNIR Drug Eluting Stent System in Coronary Stenosis

The BioNIR is a prospective, multi-center, single-blind, two-arm, randomized clinical trial. The population will consist of subjects undergoing PCI for angina (stable or unstable), silent ischemia, NSTEMI, and recent STEMI. Complex lesions are allowed. There is no limit to the number of lesions per vessel or individual lesion length; however, the total planned stenting in the coronary tree cannot exceed 100mm.

Randomization will be stratified by the presence of medically treated diabetes vs. no medically treated diabetes, acute coronary syndrome (ACS) vs. non-ACS, and by site. Lesions planned to be treated must be declared and recorded at time of randomization. Planned staged procedures, if necessary, must be declared immediately post procedure.

Clinical follow-up will be performed at 30 days, 6 months, and 1, 2, 3, 4, and 5 years post randomization. 200 patients at participating North American sites will be consented for planned angiographic follow-up at 13 months after enrollment, with 100 of these patients consented to undergo planned IVUS at baseline and at 13 months following randomization.

The primary endpoint is Target Lesion Failure (TLF) at 12 months, defined as the composite of cardiac death, target vessel-related myocardial infarction, or ischemia-driven target lesion revascularization.

Clinical Secondary Endpoints to be evaluated at 30 days, 6 months, and 1, 2, 3, 4 and 5, except as noted:

• Device, Lesion, and Procedure Success at time of baseline procedure
• TLF at 30 days, 6 months, and 2, 3, 4 and 5 years defined as the composite of cardiac death, target vessel-related MI, or ischemia-driven TLR.
• Major adverse cardiac events (MACE; the composite rate of cardiac death, any MI or ischemia-driven TLR)
• Target vessel failure (TVF; the composite rate of death, target vessel related MI or ischemia-driven TVR)
• All-cause mortality
• Cardiac death
• Myocardial Infarction
• Target Vessel Related MI
• Ischemia-driven TLR
• Ischemia-driven TVR
• Stent Thrombosis (ARC definite and probable)

Angiographic Sub-Study Secondary Endpoint to be evaluated at 13 months:

• Angiographic in-stent and in-segment late loss

IVUS Sub-Study Secondary Endpoint to be evaluated at 13 months:

• In-stent percent neointimal hyperplasia
• Stent mal-apposition

A key component of this trial will be a prospective assessment of health care resource utilization, costs and cost effectiveness. A separate cost effectiveness assessment plan describes the data collection and analysis.

Sample Size Consideration: From recent US trials of best in class DES (Xience V, Promus Element and Resolute), the 1-year TLF rate in patients with non-complex lesions not undergoing routine angiographic follow-up is approximately 3.8%. Using the assumption of the more-comers' design, the 1-year event rate will be conservatively increased by 50% (assuming enrollment rate for complex patients/lesions is 50% with double the standard event rate) - thus 5.8%. Therefore, with a one-sided 95% upper bound of the confidence interval of 3.3% (a relative 57% margin) and 1:1 randomization, enrolling 1810 patients (905 per group) provides 90% power to demonstrate non-inferiority. Assuming 95% follow-up rate at 1 year, approximately 1906 patients will be enrolled (953 in each group).

Inclusion criteria

• Patient with indication for PCI including angina/silent ischemia/NSTEMI/recent STEMI
• Non-target vessel PCI allowed prior to randomization depending on time interval and certain conditions
• Patient/legal guardian willing & able to provide informed written consent & comply with follow-up visits & testing schedule
• Target lesion(s) must be located in native coronary artery/bypass graft conduit w/visually estimated diameter ≥2.5mm to ≤4.25mm.
• Complex lesions allowed, including calcified, presence of thrombus, CTO, bifurcation (except as per exclusion criteria #30), ostial RCA, tortuous, bare metal stent restenotic, protected left main, and saphenous vein graft

Exclusion criteria

• STEMI within 24 hours of init. time of presentation to first treating hospital, or in whom enzyme levels (either CK-MB or Troponin) have not peaked
• PCI within 24 hours preceding baseline procedure
• Non-target lesion PCI in target vessel within 12 months of baseline procedure
• History of stent thrombosis
• Cardiogenic shock (persistent hypotension [systolic blood pressure <90mm/Hg for MT 30 min] or requiring pressors/hemodynamic support, including IABP)
• Subject is intubated
• Known LVEF <30%
• Relative/absolute contraindication to DAPT for 12 months (including planned surgeries that cannot be delayed, or subject indicated for chronic oral anticoagulant treatment)
• Calculated creatinine clearance <30 mL/min per Cockcroft-Gault equation (<40mL/min for subjects participating in angiographic follow-up sub-study)
• Hemoglobin <10g/dL
• Platelet count <100,000 cells/mm3 or >700,000 cells/mm3
• White blood cell (WBC) count <3,000 cells/mm3
• Clinically significant liver disease
• Active peptic ulcer/active bleeding from any site
• Bleeding from any site within prior 8 wks requiring active medical/surgical attention
• If femoral access is planned, significant peripheral arterial disease that precludes safe insertion of 6F sheath
• History of bleeding diathesis/coagulopathy/will refuse blood transfusions
• Cerebrovascular accident/transient ischemic attack within past 6 months, or any permanent neurologic defect attributed to CVA
• Known allergy to study stent components, BioNIR or Resolute
• Known allergy to protocol-required concomitant medications: aspirin/DAPT (clopidogrel, prasugrel, ticagrelor)/heparin and bivalirudin/iodinated contrast that cannot be adequately pre-medicated
• Any co-morbid condition that may cause non-compliance with protocol (e.g. dementia, substance abuse) /reduced life expectancy to <24 months (e.g. cancer, severe heart failure, severe lung disease)
• Patient participating/plans to participate in another investigational drug/device clinical trial that has not reached its primary endpoint
• Pregnant/breastfeeding women (women of child-bearing potential must have a negative pregnancy test within 1 wk before treatment)
• Women who intend to become pregnant within 12 months after baseline procedure (sexually active women of child-bearing potential must agree to use a reliable method of contraception from time of screening through 12 months post baseline procedure)
• Patient has received/is on a waiting list for an organ transplant
• Patient receiving/scheduled to receive chemotherapy within 30 days before/any time after the baseline procedure
• Patient receiving oral/intravenous immunosuppressive therapy or has known life-limiting immunosuppressive/autoimmune disease (e.g. HIV); corticosteroids are allowed
• More than 100mm length of planned stenting in the entire coronary tree
• Unprotected left main lesions ≥30%, or planned left main intervention
• Ostial LAD/LCX lesions (stenting of any diseased segment within 5mm of the unprotected left main coronary artery)
• Bifurcation lesions with planned dual stent implantation
• Stenting of lesions due to DES restenosis
• Another lesion in a target/non-target vessel (including all side branches) is present that requires/has high probability of requiring PCI within 12 months after baseline procedure