Pharmacokinetics of Everolimus in Absorb BVS in Patients With Coronary Artery Lesions

ABSORB III RCT Pharmacokinetics (PK) Sub-study

The ABSORB III PK sub-study is a prospective, open-label, non-blinded study enrolling approximately 12 subjects in up to 5 US sites. ABSORB III PK sub-study is a part of ABSORB III RCT (NCT01751906). The objective is to determine the pharmacokinetics of everolimus delivered by the Absorb BVS in a separate and non-randomized cohort of subjects who only receive Absorb BVS with a maximum of two de novo native coronary artery lesions after implantation of the Absorb BVS.

Note: The ABSORB III PK subjects will not contribute to the determination of the ABSORB III RCT primary endpoint.

To ensure the PK measurements reflect everolimus exposure due to Absorb BVS only, the PK sub-study will not allow non-target lesion treatment.

Blood Sampling Timing:

• Pre-Absorb BVS implantation: Baseline

  o Baseline is defined as prior to implantation of the first Absorb BVS; the blood sample will be drawn on the day of the index procedure either through a heparin lock, venous sheath, or venipuncture.

• Post-Absorb BVS implantation: 10 and 30 minutes, 1 hr, 2 hrs, 4 hrs, 6 hrs , 12 hrs, 24 hrs (1 day), 48 hrs (2 days), 72 hrs (3 days), 96 hrs (4 days), 120 hrs (5 days), 168 hrs (7 days), 336 hrs (14 days), and 720 hrs (30 days).

  • Post-implantation blood samples will be drawn at the time intervals stated above; timing of the post-implantation sampling will begin when the last Absorb BVS is deployed, i.e. last Absorb BVS delivery catheter is removed from the body.

Pharmacokinetic (PK) parameters will include time to maximum concentration (tmax); maximum concentration (Cmax); AUC24h: Area under the blood analyte concentration vs. time curve from time 0 up to 24 hours post placement of the last Absorb BVS; AUClast: Area under the blood analyte concentration vs. time curve from time 0 up to the last quantifiable concentration; AUC 0-infinity: Area under the blood analyte concentration vs. time curve from time zero and extrapolated to infinite time; terminal elimination rate constant (λz); terminal elimination half-life (t1/2term); drug clearance (CL).

General Inclusion Criteria:

1. 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. Evidence of myocardial. In the absence of noninvasive ischemia, FFR must be done and indicative of ischemia.
4. 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.
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 two target lesions are present, they must be present in different epicardial vessels and both must satisfy the angiographic eligibility criteria.
   2. The definition of epicardial vessels means the left anterior descending (LAD), left coronary artery (LCX), and right coronary artery (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 % diameter stenosis (DS) of ≥ 50% and < 100% with a thrombolysis in myocardial infarction (TIMI) flow of ≥ 1 and one of the following: stenosis ≥ 70%, an abnormal functional test (e.g., fractional flow reserve (FFR), stress test), unstable angina or post-infarct angina.

   1. Lesion(s) must be located in a native coronary artery with reference vessel diameter (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.

General Exclusion Criteria:

1. Any surgery requiring general anesthesia or discontinuation of aspirin and/or an Adenosine diphosphate receptor (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 creatine kinase (CK) and creatine kinase myocardial-band isoenzyme (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%

8. Subject has undergone prior percutaneous coronary intervention (PCI) within the target vessel(s) during the last 12 months.

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 glomerular filtration rate (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.

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

Angiographic Exclusion Criteria:

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

1. Lesion which prevents successful balloon pre-dilatation

2. Lesion is located in left main.

3. Aorto-ostial RCA lesion.

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.

7. Vessel contains thrombus as indicated in the angiographic images or by intravascular ultrasound (IVUS) or optical coherence tomography (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 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.