ABSORB III Randomized Controlled Trial (RCT)

The ABSORB III RCT is a prospective randomized, single-blind, multi-center trial. It is the pivotal trial to support the US pre-market approval (PMA) of Absorb™ Bioresorbable Vascular Scaffold (BVS).

The ABSORB III includes additional two trials i.e. ABSORB III PK (pharmacokinetics) sub-study and ABSORB IV RCT trial which are maintained under one protocol because both trial designs are related, ABSORB IV is the continuation of ABSORB III and the data from ABSORB III and ABSORB IV will be pooled to support the ABSORB IV primary endpoint. Both the trials will evaluate the safety and effectiveness of Absorb BVS.

ABSORB III RCT:

A. Primary Objective: The pivotal trial to support the US pre-market approval (PMA) of Absorb BVS. ABSORB III will evaluate the safety and effectiveness of the Absorb BVS System compared to the XIENCE in the treatment of subjects, including those with diabetes mellitus, with ischemic heart disease caused by up to two de novo native coronary artery lesions in separate epicardial vessels.

B. Powered Secondary Objectives:

1. Lead-In Phase Objective: To evaluate the applicability and transferability of the didactic Absorb BVS physician training plan to US clinical practice.

   The lead-in phase is a non-randomized, single-arm, open label group of up to 50 subjects treated with Absorb BVS at up to 35 US sites. The Lead-In phase will enroll/register subjects prior to the randomization phase of ABSORB III.

   The Lead-In Phase allows the treatment of up to two de novo native coronary artery lesions in different epicardial vessels with reference vessel diameter (RVD) ≥ 2.75 mm to ≤ 3.25 mm and lesion lengths ≥ 8 to ≤ 14 mm.
2. Imaging Cohort Objective: To evaluate long-term vascular function and patency of the Absorb BVS treated segments compared to XIENCE treated segments in the treatment of subjects with ischemic heart disease caused by up to two de novo native coronary artery lesions in separate epicardial vessels.

The imaging cohort-phase is a prospective, randomized (2:1 Absorb BVS to XIENCE), single-blind, multi-center trial, registering approximately 200 subjects. This includes 150 subjects for the angiographic/intravascular ultrasound (IVUS) endpoints analysis and approximately 50 subjects for optical coherence tomography (OCT) endpoints analysis. The 200 subjects are separate from the 2000 subjects included in the primary analysis. Data from two powered secondary endpoints from this cohort will support label claims of superiority of Absorb BVS as compared to XIENCE specific to vasomotion and late lumen enlargement.

All other subjects in ABSORB III unless specified will receive treatment of up to two de novo native coronary artery lesions in different epicardial vessels with RVD ≥ 2.5 mm to ≤ 3.75 mm and lesion lengths ≤ 24 mm.

Eligibility Criteria:
General Inclusion Criteria:

1. Subject must be at least 18 years of age.
2. Subject or a legally authorized representative must provide written Informed Consent prior to any study related procedure, per site requirements.
3. Subject must have evidence of myocardial ischemia (e.g., stable, unstable angina, post-infarct angina or silent ischemia) suitable for elective PCI. Subjects with stable angina or silent ischemia and \< 70% diameter stenosis must have objectives sign of ischemia as determined by one of the following, echocardiogram, nuclear scan, ambulatory ECG or stress ECG). In the absence of noninvasive ischemia, fractional flow reserve (FFR) must be done and indicative of ischemia.
4. Subject must be an acceptable candidate for coronary artery bypass graft (CABG) surgery.
5. Female subject of childbearing potential who does not plan pregnancy for up to 1 year following the index procedure. For a female subject of childbearing potential a pregnancy test must be performed with negative results known within 7 days prior to the index procedure per site standard.
6. Female subject is not breast-feeding at the time of the screening visit and will not be breast-feeding for up to 1 year following the index procedure.
7. Subject agrees to not participate in any other investigational or invasive clinical study for a period of 1 year following the index procedure.

Angiographic Inclusion Criteria:

1. One or two de novo target lesions:

   1. If there is one target lesion, a second non-target lesion may be treated but the non-target lesion must be present in a different epicardial vessel, and must be treated first with a successful, uncomplicated result prior to randomization of the target lesion.
   2. If two target lesions are present, they must be present in different epicardial vessels and both must satisfy the angiographic eligibility criteria.
   3. The definition of epicardial vessels means the LAD, LCX and RCA and their branches. Thus, the patient must not have lesions requiring treatment in e.g. both the LAD and a diagonal branch.
2. Target lesion(s) must be located in a native coronary artery with a visually estimated or quantitatively assessed %DS of ≥ 50% and \< 100% with a TIMI flow of ≥ 1 and one of the following: stenosis ≥ 70%, an abnormal functional test (e.g., fractional flow reserve, stress test), unstable angina or post-infarct angina.

   1. Lesion(s) must be located in a native coronary artery with RVD by visual estimation of ≥ 2.50 mm and ≤ 3.75 mm.
   2. Lesion(s) must be located in a native coronary artery with length by visual estimation of ≤ 24 mm.
   3. For Lead-In subjects with 3.0x18 mm Absorb BVS: lesions (s) must be located in a native coronary artery with RVD by visual estimation of ≥ 2.75 mm and ≤ 3.25 mm. The lesion length by visual estimation is ≥ 8 mm and ≤ 14 mm.

General Exclusion Criteria:

1. Any surgery requiring general anesthesia or discontinuation of aspirin and/or an ADP antagonist is planned within 12 months after the procedure.
2. Subject has known hypersensitivity or contraindication to device material and its degradants (everolimus, poly (L-lactide), poly (DL-lactide), lactide, lactic acid) and cobalt, chromium, nickel, platinum, tungsten, acrylic and fluoro polymers that cannot be adequately pre-medicated. Subject has a known contrast sensitivity that cannot be adequately pre-medicated.
3. Subject has known allergic reaction, hypersensitivity or contraindication to aspirin; or to clopidogrel and prasugrel and ticagrelor; or to heparin and bivalirudin, and therefore cannot be adequately treated with study medications.
4. Subject had an acute myocardial infarction (AMI; STEMI or NSTEMI) within 72 hours of the index procedure and both CK and CK-MB have not returned to within normal limits at the time of index procedure; or subject with stable angina or silent ischemia has CK-MB that is greater than normal limits at the time of the index procedure.
5. Subject is currently experiencing clinical symptoms consistent with new onset AMI (STEMI or NSTEMI), such as nitrate-unresponsive prolonged chest pain with ischemic ECG changes.
6. Subject has a cardiac arrhythmia as identified at the time of screening for which at least one of the following criteria is met:

   1. Subject requires coumadin or any other agent for chronic oral anticoagulation.
   2. Subject is likely to become hemodynamically unstable due to their arrhythmia.
   3. Subject has poor survival prognosis due to their arrhythmia.
7. Subject has a left ventricular ejection fraction (LVEF) \< 30% assessed by any quantitative method, including but not limited to echocardiography, MRI, Multiple-Gated Acquisition (MUGA) scan, contrast left ventriculography, PET scan, etc. LVEF may be obtained within 6 months prior to the procedure for subjects with stable CAD. For subjects presenting with ACS, LVEF must be assessed during the index hospitalization (which may include during the index procedure by contrast left ventriculography) but prior to randomization in order to confirm the subject's eligibility.
8. Subject has undergone prior PCI within the target vessel during the last 12 months. Prior PCI within the non-target vessel or any peripheral intervention is acceptable if performed anytime \>30 days before the index procedure, or between 24 hours and 30 days before the index procedure if successful and uncomplicated.
9. Subject requires future staged PCI either in target or non-target vessels or subject requires future peripheral interventions \< 30 days after the index procedure
10. Subject has received any solid organ transplants or is on a waiting list for any solid organ transplants.
11. At the time of screening, the subject has a malignancy that is not in remission.
12. Subject is receiving immunosuppressant therapy or has known immunosuppressive or severe autoimmune disease that requires chronic immunosuppressive therapy (e.g., human immunodeficiency virus, systemic lupus erythematosus, etc.). Note: corticosteroids are not included as immunosuppressant therapy.
13. Subject has previously received or is scheduled to receive radiotherapy to a coronary artery (vascular brachytherapy), or the chest/mediastinum.
14. Subject is receiving or will require chronic anticoagulation therapy (e.g., coumadin, dabigatran, apixaban, rivaroxaban or any other agent for any reason).
15. Subject has a platelet count \< 100,000 cells/mm3 or \> 700,000 cells/mm3.
16. Subject has a documented or suspected hepatic disorder as defined as cirrhosis or Child-Pugh ≥ Class B.
17. Subject has renal insufficiency as defined as an estimated GFR \< 30 ml/min/1.73m2 or dialysis at the time of screening.
18. Subject is high risk of bleeding for any reason; has a history of bleeding diathesis or coagulopathy; has had a significant gastro-intestinal or significant urinary bleed within the past six months.
19. Subject has had a cerebrovascular accident or transient ischemic neurological attack (TIA) within the past six months, or any prior intracranial bleed, or any permanent neurologic defect, or any known intracranial pathology (e.g. aneurysm, arteriovenous malformation, etc.).
20. Subject has extensive peripheral vascular disease that precludes safe 6 French sheath insertion. Note: femoral arterial disease does not exclude the patient if radial access may be used.
21. Subject has life expectancy \< 5 years for any non-cardiac cause or cardiac cause.
22. Subject is in the opinion of the Investigator or designee, unable to comply with the requirements of the study protocol or is unsuitable for the study for any reason. This includes completion of Patient Reported Outcome instruments.
23. Subject is currently participating in another clinical trial that has not yet completed its primary endpoint.
24. Subject is part of a vulnerable population who, in the judgment of the investigator, is unable to give Informed Consent for reasons of incapacity, immaturity, adverse personal circumstances or lack of autonomy. This may include: Individuals with mental disability, persons in nursing homes, children, impoverished persons, persons in emergency situations, homeless persons, nomads, refugees, and those incapable of giving informed consent. Vulnerable populations also may include members of a group with a hierarchical structure such as university students, subordinate hospital and laboratory personnel, employees of the Sponsor, members of the armed forces, and persons kept in detention.

Angiographic Exclusion Criteria:

All exclusion criteria apply to the target lesion(s) or target vessel(s).

1. Lesion which prevents successful balloon pre-dilatation, defined as full balloon expansion with the following outcomes:

   1. Residual %DS is a maximum \< 40% (per visual estimation), ≤ 20% is strongly recommended.
   2. TIMI Grade-3 flow (per visual estimation).
   3. No angiographic complications (e.g. distal embolization, side branch closure).
   4. No dissections NHLBI grade D-F.
   5. No chest pain lasting \> 5 minutes.
   6. No ST depression or elevation lasting \> 5 minutes.
2. Lesion is located in left main.
3. Aorto-ostial RCA lesion (within 3 mm of the ostium).
4. Lesion located within 3 mm of the origin of the LAD or LCX.
5. Lesion involving a bifurcation with a:

   1. side branch ≥ 2 mm in diameter, or
   2. side branch with either an ostial or non-ostial lesion with diameter stenosis \> 50%, or
   3. side branch requiring dilatation
6. Anatomy proximal to or within the lesion that may impair delivery of the Absorb BVS or XIENCE stent:

   1. Extreme angulation (≥ 90°) proximal to or within the target lesion.
   2. Excessive tortuosity (≥ two 45° angles) proximal to or within the target lesion.
   3. Moderate or heavy calcification proximal to or within the target lesion. If IVUS used, subject must be excluded if calcium arc in the vessel prior to the lesion or within the lesion is ≥ 180°.
7. Vessel contains thrombus as indicated in the angiographic images or by IVUS or OCT.
8. Lesion or vessel involves a myocardial bridge.
9. Vessel has been previously treated with a stent at any time prior to the index procedure such that the Absorb BVS or XIENCE would need to cross the stent to reach the target lesion.
10. Vessel has been previously treated and the target lesion is within 5 mm proximal or distal to a previously treated lesion.
11. Target lesion located within an arterial or saphenous vein graft or distal to any arterial or saphenous vein graft.