HARMONEE - Japan-USA Harmonized Assessment by Randomized, Multi-Center Study of OrbusNEich's Combo StEnt

Up to 50 sites are proposed in Japan and the United States to enroll 286 subjects (271 evaluable) in each of 2 arms, for a total sample size of 572 subjects (542 evaluable) who are admitted to the hospital for a planned (elective and urgent) percutaneous coronary artery intervention procedure.

After stent implantation, subjects will be contacted for follow-up at 30 days; 6 months; and 1, 2, 3, 4, and 5 years. At 12 months a clinical evaluation will be completed before cardiac catheterization and angiographic assessment.

Rationale: This study is intended to demonstrate that the Combo stent platform shows superiority to an imputed Bare Metal Stent (BMS) performance goal, noninferior effectiveness and safety vs best-in-class second-generation everolimus-eluting stent (EES) (Xience V, Xience Prime, Xience Xpedition stents; [Abbott Vascular/Abbott Vascular Japan]), and evidence of mechanistic activity of the anti-CD34-Ab endothelial progenitor cell (EPC) capture technology with healthy level of intimal tissue coverage superior to that of the best-in-class EES.

To ensure the robustness and interpretability of results, the current proposal includes a number of unique design features:

• Largest randomized Drug-Eluting Stent (DES) study ever performed in Japan
• Enriched population, including stabilized Non-ST-elevation myocardial infarction (NSTEMI) subjects with greater likelihood of plaque rupture associated with their clinical syndromes
• Collaboration between with Japan and the United States as a "Proof of Concept" program under the auspices of the Harmonization by Doing Initiative, Working Group 1 (WG 1), including concomitant enrollment in U.S.A. sites as an FDA-approved Investigational Device Exemption (IDE) study
• Head-to-head randomization against state-of-the-art EES platform control, analyzed for clinical noninferiority
• Statistical analysis vs imputed BMS analyzed for clinical superiority
• Fractional flow reserve (FFR) follow-up of 100% of subjects enrolled, providing clinically relevant physiologic assessment of all subjects for 1 year ischemia-driven Target Vessel Revascularization (TVR) analysis
• Mechanistic Optical coherence tomography (OCT) imaging observations in 140 subjects using 6 French catheters as follows:

• Cohort A (30 subjects, 1:1 Combo and EES): Mechanistic imaging observations to provide serial 6 month and 1 year OCT evaluation of healthy intimal tissue coverage, intracoronary thrombosis, and stent malapposition and quantitative coronary angiographic (QCA) analysis to assess 1 year late loss.
• Cohort B (110 subjects, 1:1 Combo and EES): Mechanistic imaging observations to assess 1 year OCT evaluation of healthy intimal tissue coverage, intracoronary thrombosis, and stent malapposition, and QCA analysis to assess 1 year late loss. Combined with the 12 month imaging of Cohort A, this study will provide OCT and QCA observations at 1 year in 140 patients, half with Combo and half with EES.
• Cohort C: 432 subjects (216 subjects per arm) will undergo all clinical follow-up assessments with FFR and angiographic assessments at 12 months. Cohort C will be the last cohort to enroll.
• In the 110 subjects in Cohort B, 30 day and 1 year human antimurine antibody (HAMA) titers will also be collected.

Inclusion criteria

To be eligible for this trial, subjects must meet all of the following criteria:

• Subject is able to verbally confirm understanding of risks, benefits, and treatment alternatives of Combo vs EES stent, and the subject or a legally authorized representative (LAR) must provide written informed consent before any study-related procedures are performed.
• Subject must be at least 20 years of age at the time of randomization.
• Subject must have clinical or functional evidence of myocardial ischemia (eg, stable or unstable angina, stabilized non-ST-elevation myocardial infarction confirmed by serum markers, ischemia by positive functional study, abnormal FFR, or a reversible change in the electrocardiogram (ECG) consistent with ischemia).
• Subject must be acceptable candidate with anatomy suitable for PCI with a DES.
• Subject agrees to return for all study-related follow-up assessments, including invasive OCT follow-up assessment at 6 months (Cohort A) and at 1 year postprocedure (Cohorts A, B, and C).
• Subject is an acceptable candidate for Coronary artery bypass grafting (CABG) surgery.

Angiographic Anatomy Criteria-

• Target lesions must be located in a native coronary artery with visually estimated diameter of 2.5 mm to 3.5 mm, inclusive, and up to 3 de novo target lesions may be treated, with a maximum of 2 de novo target lesions per epicardial vessel, with a maximum of 2 target vessels.
• Target lesions should be treatable with a single stent, and must measure 28 mm or less in length by visual estimation (2 mm or more of nondiseased tissue on either side of the target lesion should be covered by the study stent).
• If more than 1 target lesion will be treated, the reference vessel diameter and lesion length of each target lesion must meet the above criteria.
• Target lesions must be in a major artery or branch with a visually estimated stenosis of 50% or greater and less than 100% with a Thrombolysis in Myocardial Infarction (TIMI) flow of 1 or greater.
• Previous percutaneous intervention of lesions in a target vessel (including side branches) is allowed if done 9 or more months before the study procedure and greater than 10 mm from the current target lesion.
• Nonstudy percutaneous interventions for lesions in a nontarget vessel are allowed if done 9 or more months before the study procedure, in the absence of documented ischemia or angiographic restenosis related to the vessel.

Exclusion criteria

If a subject meets any of the following criteria, he or she may not be enrolled in the study:

• ST-Elevation Myocardial Infarction (STEMI) at index presentation or within 7 days of study screening.
• Subject has current unstable arrhythmias or intractable angina with ECG changes or shock requiring pressors or mechanical assist device (intraaortic balloon pump, left ventricular assist device, Impella, etc.).
• Subject has known left ventricular ejection fraction (LVEF) less than 30%.
• Subject has received a heart transplant or any other organ transplant or is on a waiting list for any organ transplant.
• Subject is receiving or scheduled to receive anticancer therapy for malignancy within 30 days before or after the procedure.
• Subject is receiving immunosuppression therapy, has known serious immunosuppressive disease (eg, human immunodeficiency virus), or has severe autoimmune disease that requires chronic immunosuppressive therapy (eg, systemic lupus erythematosus).
• Subject has known hypersensitivity or contraindication to aspirin; both heparin and bivalirudin; all available P2Y12 inhibitors (clopidogrel, prasugrel, ticlopidine, and ticagrelor); any everolimus, sirolimus, cobalt, chromium, nickel, tungsten, acrylic, or fluoro polymers; or hypersensitivity to contrast media that cannot be adequately premedicated.
• Subject has previously received murine therapeutic antibodies and exhibited sensitization through the production of human anti-mouse antibodies (HAMAs).
• Subject has elective surgery planned within the first 12 months after the procedure that will require interruption or discontinuation of planned Dual Antiplatelet Therapy (DAPT).
• Subject has known platelet count less than 100,000 cells/mm3 or greater than 700,000 cells/mm3, a white blood cell count of less than 3000 cells/mm3, or documented or suspected liver disease (including laboratory evidence of hepatitis).
• Subject has known renal insufficiency (eg, serum creatinine level of greater than 2.5 mg/dL or subject is on dialysis).
• Subject has history of bleeding diathesis or coagulopathy or will refuse blood transfusions.
• Subject has had a cerebrovascular accident or transient ischemic neurological attack within the past 6 months.
• Subject has had a significant gastrointestinal or urinary bleed within the past 6 months.
• Subject has known extensive peripheral vascular disease that precludes safe 6 French sheath insertion.
• Known other medical illness (eg, cancer, chronic infectious disease, severe vascular disease, or congestive heart failure) or known history of substance abuse (alcohol, cocaine, heroin, etc.) that may cause noncompliance with the protocol, confound the data interpretation, or is associated with a life expectancy of less than 1 year.
• Currently participating in another clinical study that has not yet reached its primary endpoint.
• Currently pregnant or breast-feeding or is planning pregnancy in the period up to 1 year following index procedure. Female subjects of childbearing potential must have a negative pregnancy test within 7 days before the index procedure.

Angiographic Exclusion Criteria-

If the target lesion meets any of the following criteria, the subject may not be enrolled in the study:

• Unprotected left main coronary artery location.
• Unprotected ostial (located within 2 mm of the origin) left anterior descending artery or left circumflex.
• Located within an arterial or saphenous vein graft or graft anastomosis, distal to a diseased arterial or saphenous vein graft (visually estimated graft diameter stenosis greater than 40%).
• Involves a bifurcation in which the side branch is 2 mm or greater in diameter AND would be covered by the planned stent.
• Involves a side branch requiring predilation.
• Total occlusion (TIMI flow 0) before wire crossing.
• Extreme tortuosity proximal to or within the lesion.
• Extreme angulation (90º or greater) proximal to or within the lesion.
• Heavy calcification, defined as multiple persisting opacifications of the coronary wall visible in more than one projection surrounding the complete lumen of the coronary artery at the site of the lesion.
• Restenotic vessel from previous intervention.
• Received brachytherapy in any epicardial vessel (including side branches).
• Target vessel contains angiographically visible thrombus.
• Serial lesions or diffuse disease with high probability of bailout requiring 3 or more stents in a single vessel, more than 5 stents per subject, or more than 2 vessels.
• Target or nontarget vessel lesion (including all side branches) is present with a high probability of requiring PCI within 12 months after the index procedure.
• Stent overlapping is a planned treatment of the target lesion.