Safety and Effectiveness of the Orsiro Sirolimus Eluting Coronary Stent System in Subjects With Coronary Artery Lesions

The objective of this study is to assess the safety and efficacy of the Orsiro Sirolimus Eluting Coronary Stent System in the treatment of subjects with up to three native de novo or restenotic (standard PTCA only) coronary artery lesions compared to the Xience coronary stent system.

The BIOTRONIK BIOFLOW-V clinical trial is a prospective, multicenter, randomized, controlled trial combining data on the randomized subjects with data from two historical studies by employing a Bayesian approach.

Subjects with CAD that qualify for PCI with stenting will be screened per the protocol inclusion and exclusion criteria to achieve a total of up to 1,400 randomized subjects. Eligible subjects will be randomized in a 2:1 ratio, stratified by study center, to undergo percutaneous coronary revascularization with either the Orsiro Sirolimus Eluting Stent System (treatment group) or the Xience Everolimus Eluting Stent System (control group).

Subjects may receive treatment of up to three target lesions, one or two target lesions per target vessel, for a maximum of two target vessels. The target lesion(s) must be de novo or restenotic lesion(s) of ≤ 36 mm in length in native coronary artery(ies), with a reference vessel diameter of 2.25-4.0 mm. Treatment of restenotic lesions is allowed provided that the target lesion was previously treated with PTCA only. All treatment with study stents is to be performed during a single index procedure. Note: Concurrent treatment of non-target lesions during the index procedure is not allowed.

Randomized subjects will have clinical follow-up at 1 month, 6 months, 12 months and at 2, 3, 4 and 5 years following the index procedure.

To assess the non-inferiority of the Orsiro stent compared to the Xience stent, BIOFLOW-V randomized subjects will be combined with historical subjects from the BIOFLOW-II and BIOFLOW-IV randomized trials employing a Bayesian approach. Only subjects who meet all clinical and angiographic eligibility criteria of the BIOFLOW-V trial will be included in the analysis.

Eligibility Criteria:
Inclusion Criteria:

1. Subject is ≥18 years or the minimum age required for legal adult consent in the country of enrollment.
2. Subject is an acceptable candidate for PCI.
3. Subject is an acceptable candidate for CABG.
4. Subject has clinical evidence of ischemic heart disease, stable or unstable angina pectoris or documented silent ischemia.
5. Subject is eligible for dual anti-platelet therapy treatment with aspirin plus either, clopidogrel, prasugrel, ticagrelor or ticlopidine.
6. Subject has provided written informed consent.
7. Subject is willing to comply with study follow-up requirements.

Each target lesion/vessel must meet all of the following angiographic criteria for the subject to be eligible for the trial:

1. Subject has up to three target lesions in up to two separate target vessels (two target lesions in one vessel and one target lesion in a separate vessel).
2. Target lesion must be de novo or restenotic lesion in native coronary artery; restenotic lesion must have been treated with a standard PTCA only.
3. Target lesion must be in major coronary artery or branch (target vessel).
4. Target lesion must have angiographic evidence of ≥ 50% and \< 100% stenosis (by operator visual estimate). If the target lesion is \< 70% stenosed, clinical evidence of ischemia by positive functional study, CT, electrocardiography, FFR, or post infarct angina.
5. TIMI flow \> 1.
6. Target lesion must be ≤ 36 mm in length by operator visual estimate.
7. Target vessel RVD of 2.25-4.0 mm by operator visual estimate.
8. Target lesion must be treatable with a maximum of two overlapping stents.

Exclusion Criteria:

1. Subject has clinical symptoms and/or electrocardiogram (ECG) changes consistent with acute ST elevation myocardial infarction (STEMI) within 72 hours prior to the index procedure. Hemodynamically stable non-STEMI (NSTEMI) subjects are eligible for study enrollment.
2. Subject is hemodynamically unstable.
3. Subject is pregnant and/or breastfeeding or intends to become pregnant during the duration of the study.
4. Subject has a known allergy to contrast medium that cannot be adequately pre-medicated, or any known allergy to thienopyridine, aspirin, both heparin and bivalirudin, L-605 cobalt-chromium (Co-Cr) alloy or one of its major elements (cobalt, chromium, tungsten and nickel), acrylic, fluoropolymers, silicon carbide, PLLA, sirolimus or everolimus.
5. Revascularization of any target vessel within 9 months prior to the index procedure or previous PCI of any non-target vessel within 30 days prior to the index procedure.
6. Planned treatment of a lesion not meeting angiographic inclusion and exclusion criteria during the index procedure or after the index procedure.
7. Planned surgery within 6 months of index procedure unless dual antiplatelet therapy can be maintained throughout the peri-surgical period.
8. History of a stroke or transient ischemic attack (TIA) within 6 months prior to the index procedure.
9. Subjects with active bleeding disorders, active coagulopathy, or any other reason, who are ineligible for DAPT.
10. Subject will refuse blood transfusions.
11. Subject has documented left ventricular ejection fraction (LVEF) \< 30% within 90 days prior to the index procedure.
12. Subject is dialysis-dependent.
13. Subject has impaired renal function (i.e., blood creatinine \> 2.5 mg/dL or 221 μmol/L determined within 7 days prior to the index procedure).
14. Subject has leukopenia (i.e. \< 3,000 white blood cells/mm3), thrombocytopenia (i.e. \< 100,000 platelets/mm3) or thrombocytosis (i.e. \> 700,000 platelet/mm3).
15. Subject is receiving oral or intravenous immunosuppressive therapy (inhaled steroids are permitted), or has known life-limiting immunosuppressive or autoimmune disease (e.g., human immunodeficiency virus, systemic lupus erythematosus; diabetes mellitus is permitted).
16. Subject is receiving chronic anticoagulation (e.g. coumadin, dabigatran, apixaban, rivaroxaban or any other agent).
17. Subject has life expectancy of \< 1 year.
18. Subject is participating in another investigational (medical device or drug) clinical study. Subjects may be concurrently enrolled in a post-market study, as long as the post-market study device, drug or protocol does not interfere with the investigational treatment or protocol of this study.
19. In the investigator's opinion, subject will not be able to comply with the follow-up requirements.

Subjects will be excluded from the trial if any of the target lesions/vessels meets any of the following angiographic criteria:

1. Target lesion is located within a saphenous vein graft or arterial graft.
2. Target lesion is a restenotic lesion that was previously treated with a bare metal or drug eluting stent (in-stent restenosis).
3. Target lesion has any of the following characteristics:

   1. Lesion location is within the left main coronary artery, or within 3 mm of the origin of the left anterior descending (LAD) or left circumflex (LCX).
   2. Involves a side branch of \> 2.0 mm in diameter. Note: Lesions within 3 mm of the origin of the right coronary artery may be treated.
4. Target vessel/lesion is excessively tortuous/angulated or is severely calcified, that would prevent complete inflation of an angioplasty balloon. This assessment should be based on visual estimation.
5. Target vessel has angiographic evidence of thrombus.
6. Target lesion is totally occluded (100% stenosis).
7. Target vessel was treated with brachytherapy any time prior to the index procedure.