ABSORB GT1 BIORESORBABLE VASCULAR SCAFFOLD (BVS) SYSTEM
Device Facts
| Record ID | P150023 |
|---|---|
| Device Name | ABSORB GT1 BIORESORBABLE VASCULAR SCAFFOLD (BVS) SYSTEM |
| Applicant | Abbott Vascular, Inc. |
| Product Code | PNY · Cardiovascular |
| Decision Date | Jul 5, 2016 |
| Decision | APWD |
| Device Class | Class 3 |
| Attributes | Therapeutic, Real-World Evidence |
Real-World Evidence
| Submission | Device | Sponsor | RWD Sources | RWE Use Summary | Key Tags |
|---|---|---|---|---|---|
| P150023 · Jul 5, 2016 | ABSORB GT1 BIORESORBABLE VASCULAR SCAFFOLD (BVS) SYSTEM | Abbott Vascular, Inc. | Global continued access registry (ABSORB EXTEND) | The ABSORB EXTEND registry was used to assess the safety and performance of the Absorb BVS in a broader patient population, including those with more complex lesions, to supplement the primary pivotal clinical trial data. | Registry; Continued access registry; Safety and performance assessment |
Clinical Evidence
| Study Design | Population | Comparator | Key Endpoints |
|---|---|---|---|
| ABSORB EXTEND; Prospective, non-randomized, single arm, open-labeled multicenter clinical study (registry); Follow-up/Duration: 3 years; Study Period: January 11, 2010 to October 2, 2013 | Subjects with a maximum of two de novo native coronary artery lesions, target lesions >22 mm and ≤28 mm in length, and reference vessel sizes suitable for treatment with Absorb.; Sample Size: 812 subjects; Number of Sites: Up to 58 global sites | Not applicable for this study | Acute success, Major Adverse Cardiac Event (MACE), Target Lesion Failure (TLF), and Target Vessel Failure (TVF) |
Indications for Use
The Absorb GT1 Bioresorbable Vascular Scaffold (BVS) is a temporary scaffold that will fully resorb over time and is indicated for improving coronary luminal diameter in patients with ischemic heart disease due to de novo native coronary artery lesions (length ≤ 24 mm) with a reference vessel diameter of ≥ 2.5 mm and ≤ 3.75 mm.
Device Story
Absorb GT1 BVS is a temporary, bioresorbable coronary scaffold designed to improve luminal diameter in ischemic heart disease. It consists of a poly(L-lactide) (PLLA) scaffold coated with a matrix of everolimus and poly(D,L-lactide) (PDLLA). The device is delivered via a rapid-exchange catheter system featuring platinum marker beads for fluoroscopic visualization. During percutaneous coronary intervention (PCI), the physician deploys the scaffold at the lesion site; the scaffold provides mechanical support and elutes everolimus to inhibit neointimal proliferation. The scaffold is designed to fully resorb over time, potentially offering long-term benefits by restoring vessel vasomotion. The device is used in a cardiac catheterization lab by interventional cardiologists. Clinical decision-making relies on angiographic assessment of vessel size; the device is contraindicated in small vessels (< 2.5 mm) due to increased risks of myocardial infarction and scaffold thrombosis.
Clinical Evidence
Evidence based on the ABSORB III pivotal RCT (n=2008) comparing Absorb to XIENCE. Primary endpoint (1-year TLF) met non-inferiority (7.8% vs 6.1%, p=0.007). Secondary endpoints (angina, revascularization) showed comparable performance. Supportive data from ABSORB Cohort B, EXTEND, II, and Japan trials. Post-hoc analysis identified safety signals (higher MI/thrombosis) in vessels < 2.25 mm (QCA). PK sub-study confirmed systemic everolimus exposure is low and transient.
Technological Characteristics
Scaffold: Poly(L-lactide) (PLLA). Coating: Everolimus (100 μg/cm²) and poly(D,L-lactide) (PDLLA). Markers: Platinum beads. Delivery: Rapid-exchange catheter with hydrophilic coating. Sterilization: E-beam radiation. MR Compatibility: MR Conditional (3T or less). Software: None.
Indications for Use
Indicated for patients ≥ 18 years old with ischemic heart disease due to de novo native coronary artery lesions (length ≤ 24 mm, reference vessel diameter 2.5–3.75 mm). Contraindicated in patients unable to tolerate procedural anticoagulation or antiplatelet regimens, or with hypersensitivity to everolimus, PLLA, PDLLA, platinum, or contrast agents.
Regulatory Classification
Identification
An absorbable scaffold with a drug coating placed via a delivery catheter into the coronary artery or saphenous vein graft to maintain the lumen. The drug coating is intended to inhibit restenosis.
Reference Devices
- XIENCE V (P070015)
- XIENCE Xpedition
- XIENCE Alpine
- Absorb BVS
Submission Summary (Full Text)
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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)
I. GENERAL INFORMATION
Device Generic Name: Absorbable Coronary Drug-Eluting Stent
Device Trade Name: Absorb GT1™ Bioresorbable Vascular Scaffold (BVS) System
Device Procode: PNY
Applicant’s Name and Address: Abbott Vascular
3200 Lakeside Drive
Santa Clara, CA 95054
Date(s) of Panel Recommendation: March 15, 2016
Premarket Approval Application (PMA) Number: P150023
Date of FDA Notice of Approval: July 5, 2016
II. INDICATIONS FOR USE
The Absorb GT1 Bioresorbable Vascular Scaffold (BVS) is a temporary scaffold that will fully resorb over time and is indicated for improving coronary luminal diameter in patients with ischemic heart disease due to de novo native coronary artery lesions (length ≤ 24 mm) with a reference vessel diameter of ≥ 2.5 mm and ≤ 3.75 mm.
III. CONTRAINDICATIONS
The Absorb GT1 BVS System is contraindicated for use in:
- Patients who cannot tolerate, including allergy or hypersensitivity to, procedural anticoagulation or the post-procedural antiplatelet regimen.
- Patients with hypersensitivity or contraindication to everolimus or structurally-related compounds, or known hypersensitivity to scaffold components (poly(L-lactide), poly(D,L-lactide), platinum) or with contrast sensitivity.
IV. WARNINGS AND PRECAUTIONS
The warnings and precautions can be found in the Absorb GT1 BVS System labeling.
V. DEVICE DESCRIPTION
The Absorb GT1 Bioresorbable Vascular Scaffold (BVS) System is composed of the following components:
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- A bioresorbable poly(L-lactide) (PLLA) scaffold
- A coating comprised of the active pharmaceutical ingredient everolimus and bioresorbable poly(D,L-lactide) (PDLLA)
- Four (4) platinum marker beads, two (2) embedded at both the proximal and distal ends of the scaffold for radiopacity
- A scaffold delivery system that leverages technology of the XIENCE family of products and incorporates design features from the Absorb BVS, XIENCE Xpedition®, and XIENCE Alpine® delivery systems
The product description for the Absorb GT1 BVS System is detailed below in Table V-1. The Absorb GT1 BVS System size matrix incorporates a small and medium scaffold design. The small design is available in 2.5 and 3.0 mm diameters in lengths of 8, 12, 18, 23, and 28 mm. The medium design is available in a 3.5 mm diameter in lengths of 12, 18, 23, and 28 mm. The Absorb GT1 BVS System is available in a Rapid Exchange (RX) configuration.
Table V-1 Absorb GT1 BVS System Product Description
| Available Stent Lengths (mm) | 8, 12, 18, 23, and 28 | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| Available Stent Diameters (mm) | 2.5, 3.0, and 3.5 | | | | | |
| Stent Material | Poly(L-lactide) | | | | | |
| Drug Component | Scaffold Design | Scaffold Diameter (mm) | Scaffold Length (mm) | Scaffold Surface Area (cm2) | Drug Dose Density (μg/cm2) | Target Drug Amount (μg) |
| | Small | 2.5 / 3.0 | 8 | 0.76 | 100 | 76 |
| | | | 12 | 1.14 | | 114 |
| | | | 18 | 1.81 | | 181 |
| | | | 23 | 2.28 | | 228 |
| | | | 28 | 2.76 | | 276 |
| | Medium | 3.5 | 12 | 1.35 | | 135 |
| | | | 18 | 1.97 | | 197 |
| | | | 23 | 2.46 | | 246 |
| | | | 28 | 3.08 | | 308 |
| | Delivery System Working Length | 143 cm | | | | |
| Delivery System | Single access port to inflation lumen; guide wire exit notch is located 26 cm from tip; designed for guide wires ≤ 0.014”. | | | | | |
| Scaffold Delivery System Balloon | A compliant, tapered balloon, with two radiopaque markers located on the catheter shaft to indicate balloon positioning and expanded scaffold length | | | | | |
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Table V-1 Absorb GT1 BVS System Product Description
| Balloon Inflation Pressure | Rated Burst Pressure (RBP): 16 atm (235 psi) | |
| --- | --- | --- |
| | Stent Diameter (mm) | In vitro Stent Nominal Pressure (atm) |
| | 2.5 | 6 |
| | 3.0 | 7 |
| | 3.5 | 6 |
| Guiding Catheter Inner Diameter | ≥ 6 F (0.066”) | |
| Catheter Shaft Outer Diameter | Distal: 0.039” ± 0.002” (0.99 mm ± 0.05 mm) Proximal: ≤ 0.029” (0.74 mm) | |
# A. Device Component Description
The Absorb GT1 BVS System consists of a polymeric scaffold mounted on a scaffold delivery system (SDS). The scaffold is manufactured from the bioresorbable polymer poly(L-lactide) (PLLA), a semicrystalline polymer whose degree of crystallinity and crystalline microstructure are dictated by the thermal and deformation history during processing. Two (2) platinum markers are embedded at each end ring to enable fluoroscopic visualization.
The SDS incorporates design features from the Absorb BVS, XIENCE Xpedition, and XIENCE Alpine delivery systems. The delivery system has a rapid-exchange (RX) design with the balloon and scaffold at the distal end of the catheter. For the RX design, the proximal lumen provides for inflation of the balloon with contrast medium and the central distal lumen permits a guidewire to facilitate advancement of the catheter. The distal catheter shaft, the tip, and tapers of the balloon are coated with HYDROCOAT™ Hydrophilic Coating.
Radiopaque markers are positioned underneath the balloon to provide accurate positioning of the scaffold / balloon in the artery. The balloon is designed to deliver an expandable scaffold of known diameter and length at specified pressures. Markers located on the proximal outer shafts help physicians gauge the delivery catheter position relative to the guiding catheter tip. An adaption arm on the proximal end provides access to the inflation lumen. The SDS is designed with a luer-lock fitting to facilitate connection to an inflation device.
# B. Drug Component Description
The Absorb GT1 BVS is coated with a drug / polymer matrix that consists of 50 wt% PDLLA and 50 wt% of the active pharmaceutical ingredient everolimus, the same drug utilized for the XIENCE family of products. Neither a primer coat nor a topcoat layer is utilized for the Absorb GT1 BVS. The Absorb GT1 BVS also utilizes the same drug dose density (100 $\mu$ g/cm²) and similar coating technologies as the XIENCE family of products.
# B1. Everolimus
Everolimus (Chemical name: 40-O-(2-hydroxyethyl)-rapamycin) (Figure V-1) is a novel semisynthetic macrolide immunosuppressant obtained through chemical modification of rapamycin. Rapamycin (INN: Sirolimus) is a secondary macrolide metabolite that is produced by certain actinomycete strains.
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Figure V-1 Chemical Structure of Everolimus
# B2. Inactive Ingredients
The Absorb GT1 BVS System contains poly(D,L-lactide) (PDLLA), an amorphous polymer containing an equimolar mixture of D- and L lactide. PDLLA is used to contain and control the release of everolimus. PDLLA is characterized by a lower tensile strength and higher elongation than poly(L-lactide) (PLLA) due to its amorphous nature.
# C. Mechanism of Action
The mechanism by which the Absorb GT1 BVS inhibits neointimal growth as seen in preclinical and clinical studies has not been established. At the cellular level, everolimus inhibits growth factor-stimulated cell proliferation. At the molecular level, everolimus forms a complex with the cytoplasmic protein FKBP-12 (FK 506 Binding Protein). This complex binds to and interferes with FRAP (FKBP-12 Rapamycin Associated Protein), also known as mTOR (mammalian Target Of Rapamycin), leading to inhibition of cell metabolism, growth and proliferation by arresting the cell cycle at the late G1 stage.
# VI. ALTERNATIVE PRACTICES AND PROCEDURES
There are several other alternatives for the treatment of patients with coronary artery disease including exercise, diet, drug therapy, percutaneous coronary interventions (i.e., balloon angioplasty, atherectomy, bare metal stents, and drug-eluting stents), and coronary artery bypass graft (CABG) surgery. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.
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# VII. MARKETING HISTORY
The Absorb GT1 BVS System is commercially available in the following countries:
- AUSTRIA
- BAHRAIN
- BANGLADESH
- BELGIUM
- BRAZIL
- BRUNEI
- CANADA
- CHILE
- COLOMBIA
- CZECH REPUBLIC
- DENMARK
- DOMINICAN REP.
- ESTONIA
- FINLAND
- FRANCE
- GEORGIA
- GERMANY
- HONG KONG
- HUNGARY
- IRELAND
- ITALY
- JORDAN
- KUWAIT
- LATVIA
- LEBANON
- LITHUANIA
- LUXEMBOURG
- MALAYSIA
- MALTA
- MAURITIUS
- NETHERLANDS
- NORWAY
- OMAN
- PAKISTAN
- POLAND
- PORTUGAL
- QATAR
- REUNION
- ROMANIA
- SAUDI ARABIA
- SERBIA
- SLOVAKIA
- SPAIN
- SWEDEN
- SWITZERLAND
- THAILAND
- TUNISIA
- TURKEY
- UNIT.ARAB EMIR.
- UNITED KINGDOM
- VIETNAM
The Absorb BVS System* is commercially available in the following countries:
- ARGENTINA
- AUSTRALIA
- AUSTRIA
- BAHRAIN
- BANGLADESH
- BELARUS
- BELGIUM
- BRAZIL
- BRUNEI
- BULGARIA
- CHILE
- COLOMBIA
- COSTA RICA
- CYPRUS
- CZECH REPUBLIC
- DENMARK
- DOMINICAN REP.
- EGYPT
- ESTONIA
- FINLAND
- FRANCE
- GEORGIA
- GERMANY
- GREECE
- HONG KONG
- HUNGARY
- INDIA
- INDONESIA
- IRAN
- IRAQ
- IRELAND
- ISRAEL
- ITALY
- JORDAN
- KAZAKHSTAN
- KOSOVO
- KUWAIT
- LEBANON
- LIBYA
- LITHUANIA
- LUXEMBOURG
- MALAYSIA
- MALTA
- MAURITIUS
- MEXICO
- MOROCCO
- NEPAL
- NETHERLANDS
- NEW ZEALAND
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- NORWAY
- OMAN
- PAKISTAN
- PANAMA
- PHILIPPINES
- POLAND
- PORTUGAL
- QATAR
- REP. OF ARMENIA
- REUNION
- ROMANIA
- RUSSIAN FED.
- SAUDI ARABIA
- SERBIA
- SINGAPORE
- SLOVAKIA
- SOUTH KOREA
- SPAIN
- SWEDEN
- SWITZERLAND
- TAIWAN
- THAILAND
- TUNISIA
- TURKEY
- UKRAINE
- UNIT. ARAB EMIR.
- UNITED KINGDOM
- URUGUAY
- VIETNAM
*Note: The Absorb BVS System has the same scaffold as the Absorb GT1 BVS and differs from the Absorb GT1 BVS only in the delivery system.*
There have been no removals of the Absorb device from commercial distribution due to safety or effectiveness reasons. There was one (1) Field Safety Notice for commercial products issued on December 7th, 2015 that highlighted updates to the Instructions For Use to improve scaffold deployment.
## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH
Adverse events that may be associated with percutaneous coronary intervention (PCI), and the use of a coronary scaffold in native coronary arteries include, but are not limited to, the following:
- Allergic reaction or hypersensitivity to latex, contrast agent, anesthesia, device materials (platinum, iridium, palladium, rhodium and gold, or polymer [poly(L-lactide) (PLLA), polymer poly(D,L-lactide) (PDLLA)]), and drug reactions to everolimus, anticoagulation, or antiplatelet drugs
- Vascular access complications which may require transfusion or vessel repair, including:
- Catheter site reactions
- Bleeding (ecchymosis, oozing, hematoma, hemorrhage, retroperitoneal hemorrhage)
- Arteriovenous fistula, pseudoaneurysm, aneurysm, dissection, perforation / rupture
- Embolism (air, tissue, plaque, thrombotic material or device)
- Peripheral nerve injury
- Peripheral ischemia
- Coronary artery complications which may require additional intervention, including:
- Total occlusion or abrupt closure
- Arteriovenous fistula, pseudoaneurysm, aneurysm, dissection, perforation / rupture
- Tissue prolapse / plaque shift
- Embolism (air, tissue, plaque, thrombotic material or device)
- Coronary or scaffold thrombosis (acute, subacute, late, very late)
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○ Stenosis or restenosis
- Pericardial complications which may require additional intervention, including:
- Cardiac tamponade
- Pericardial effusion
- Pericarditis
- Cardiac arrhythmias (including conduction disorders, atrial and ventricular arrhythmias)
- Cardiac ischemic conditions (including myocardial ischemia, acute myocardial infarction, coronary artery spasm and unstable or stable angina pectoris)
- Stroke / Cerebrovascular accident (CVA) and Transient Ischemic Attack (TIA)
- System organ failures:
- Cardio-respiratory arrest
- Cardiac failure
- Cardiopulmonary failure (including pulmonary edema)
- Renal insufficiency / failure
- Shock
- Blood cell disorders (including Heparin Induced Thrombocytopenia [HIT])
- Hypotension or hypertension
- Infection
- Nausea and vomiting
- Palpitations, dizziness, and syncope
- Chest pain
- Fever
- Pain
- Death
Zortress®, the oral formulation of everolimus developed by Novartis Pharmaceuticals Corporation, has been evaluated in clinical trials and is approved in the United States for the prevention of organ rejection in adult kidney transplant recipients at the dose of 1.5 mg/day.
Outside the U.S., Zortress is sold under the brand name Certican® in more than 70 countries. Everolimus is also approved in the United States under the name Afinitor® for patients with advanced renal cell carcinoma (cancer), after failure of treatment with sunitinib or sorafenib, at doses of 5 to 20 mg/day when taken by mouth. The following list includes the known risks of everolimus at the oral doses listed above:
- Abdominal pain
- Anemia
- Angioedema (increased risk with concomitant ACE inhibitor use)
- Anorexia
- Arterial thrombotic events
- Asthenia
- Bleeding and coagulopathy
- Constipation
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- Cough
- Diabetes mellitus
- Diarrhea
- Dry skin
- Dysgeusia
- Dyslipidemia (including hyperlipidemia and hypercholesterolemia)
- Dyspepsia
- Dyspnea
- Dysuria
- Embryo-fetal toxicity
- Epistaxis
- Erythema
- Erythroderma
- Fatigue
- Headache
- Hematuria
- Hepatic Artery Thrombosis (HAT)
- Hepatic disorders (including hepatitis and jaundice)
- Hypersensitivity to everolimus active substance, or to other rapamycin derivatives
- Hypertension
- Infections and serious infections (bacterial, fungal, viral or protozoal infections, including infections with opportunistic pathogens). Polyoma virus-associated nephropathy (PVAN), JC virus-associated progressive multiple leukoencephalopathy (PML), fatal infections, and sepsis have been reported in patients treated with oral everolimus
- Insomnia
- Interaction with strong inhibitors and inducers of CYP3A4 or PgP
- Laboratory test abnormalities (elevations of serum creatinine, proteinuria, hyperkalemia, hypokalemia, hyperglycemia, dyslipidemia including hypercholesterolemia and hypertriglyceridemia, hypomagnesemia, hypophosphatemia, abnormal liver function tests, reduction in hemoglobin, lymphocytes, neutrophils, and platelets)
- Leukopenia
- Lymphoma and other malignancies (including skin cancer)
- Male infertility (azospermia and/or oligospermia)
- Mucosal inflammation (including oral ulceration and oral mucositis)
- Nausea
- Nephrotoxicity (in combination with cyclosporine)
- Neutropenia
- Non-infectious pneumonitis (including interstitial lung disease)
- Oral ulcerations
- Pain: extremity, incision site and procedural, back, chest, musculoskeletal
- Pancreatitis
- Pericardial effusion
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- Peripheral edema
- Pleural effusion
- Pneumonia
- Proteinuria
- Pruritis
- Pyrexia
- Rash
- Renal arterial and venous thrombosis
- Renal failure
- Stomatitis
- Thrombocytopenia
- Thrombotic microangiopathy (TMA)/Thrombotic thrombocytopenic purpura (TTP)/ Hemolytic uremic syndrome (HUS) – increased risk with concomitant cyclosporine use
- Tremor
- Upper respiratory tract infection
- Urinary tract infection
- Venous thromboembolism
- Vomiting
- Wound healing complications (including delayed wound healing, wound infections and lymphocele)
Live vaccines should be avoided and close contact with those that have had live vaccines should be avoided. There may be other potential adverse events that are unforeseen at this time.
## IX. SUMMARY OF NONCLINICAL STUDIES
### A. Laboratory Studies
#### A1. Biocompatibility Studies
ISO 10993-1-specified biocompatibility tests for a blood contact permanent implant (>30 days) were performed for the Absorb GT1 BVS with everolimus (drug scaffold) and without everolimus (polymer only scaffold). These tests include cytotoxicity, sensitization, irritation or intracutaneous reactivity, systemic toxicity (acute), subchronic toxicity, genotoxicity, implantation, and hemocompatibility. The Absorb GT1 BVS passed all test acceptance criteria (Table IX-1).
ISO 10993-1 specified biocompatibility tests for externally communicating devices contacting circulating blood (≤24 hours) were performed for the Absorb GT1 BVS scaffold delivery system (SDS). These tests include cytotoxicity, sensitization, irritation or intracutaneous reactivity, systemic toxicity (acute), and hemocompatibility. The SDS passed all test acceptance criteria (Table IX-1).
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All biocompatibility testing was conducted in accordance with one or more of the following regulations and guidance documents:
- ISO 10993 Biological Evaluation of Medical Devices
- Guidance for Industry and Food and Drug Administration Staff – Use of International Standard ISO-10993-1, “Biological Evaluation of Medical Devices Part 1: Evaluation and Testing Within a Risk Management Process”
- Good Laboratory Practices Regulations (21 CFR, part 58)
Table IX-1 Biocompatibility Test Summary
| Test | Test Description | Test Article and Results |
| --- | --- | --- |
| Cytotoxicity | ISO 10993-5: MEM Extract or Direct Contact | • Drug scaffold: Pass (non-cytotoxic)
• Polymer only scaffold: Pass (non-cytotoxic)
• Optimized delivery system: Pass (non-cytotoxic) |
| Sensitization | ISO 10993-10: Maximization Test for Delayed Hypersensitivity | • Drug scaffold: Pass (non-sensitizing)
• Polymer only scaffold: Pass (non-sensitizing)
• Optimized Delivery System: Pass (non-sensitizing) |
| Intracutaneous Reactivity | ISO 10993-10: Intracutaneous (Intradermal) Reactivity Test | • Drug scaffold: Pass (non-irritating)
• Polymer only scaffold: Pass (non-irritating)
• Optimized delivery system: Pass (non-irritating) |
| Systemic Toxicity (Acute) | ISO 10993-11: Acute Systemic Toxicity | • Drug scaffold: Pass (non-toxic)
• Polymer only scaffold: Pass (non-toxic)
• Optimized delivery system: Pass (non-toxic) |
| | ISO 10993-11 and USP <151>: Pyrogen Test (Material Mediated) | • Drug scaffold: Pass (non-pyrogenic)
• Polymer only scaffold: Pass (non-pyrogenic)
• Optimized delivery system: Pass (non-pyrogenic) |
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Table IX-1 Biocompatibility Test Summary
| Test | Test Description | Test Article and Results |
| --- | --- | --- |
| Hemocompatibility | ISO 10993-4: Hemolysis Direct and Indirect Contact | • Drug scaffold: Pass (non-hemolytic)
• Polymer only scaffold: Pass (non-hemolytic)
• Optimized Delivery System: Pass (non-hemolytic) |
| | ISO 10993-4: Coagulation (PT and PPT) | • Drug scaffold: Pass
• Polymer only scaffold: Pass
• Optimized delivery system: Pass |
| | ISO 10993-4: Complement Activation (C3a and SC5b-9) | • Drug scaffold: Pass
• Polymer only scaffold: Pass
• Optimized delivery system: Pass |
| Implantation | ISO 10993-11: Subchronic Toxicity - 90 day implantation | • Polymer only scaffold: Pass (non- toxic) |
| Genotoxicity | ISO 10993-3: Bacterial Reverse Mutation Assay (AMES Test) | • Drug scaffold: Pass (non-mutagenic)
• Polymer only scaffold: Pass (non-mutagenic) |
| | ISO 10993-3: In Vitro Chromosomal Aberration | • Drug scaffold: Pass (non-mutagenic)
• Polymer only scaffold: Pass (non-mutagenic) |
| | ISO 10993-3: Clastogenicity in Mammalian Cells (Forward Mutation) | • Drug scaffold: Pass (non-mutagenic)
• Polymer only scaffold: Pass (non-mutagenic) |
| | ISO 10993-3: Mammalian Erythrocyte Micronucleus Test | • Drug scaffold: Pass (non-mutagenic)
• Polymer only scaffold: Pass (non-mutagenic) |
Since the Absorb GT1 BVS uses the identical drug substance (everolimus) as the XIENCE family of stents at the same drug dose density of $100\ \mu\mathrm{g}/\mathrm{cm}^2$, carcinogenicity and teratology studies in the original XIENCE V PMA submission (P070015) were leveraged for the Absorb GT1 BVS. Degradation characterization and impact on biocompatibility were assessed with long term preclinical studies (up to 48 months) in porcine coronary arteries. All the studies met pre-specified study acceptance criteria and support the biocompatibility of the Absorb GT1 BVS.
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# A2. In Vitro Engineering Testing
In vitro engineering testing, in accordance with the April 2010 FDA "Guidance for Industry and FDA Staff - Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems," was conducted on the Absorb GT1 BVS System. This testing is summarized in Table IX-2. "Pass" denotes that the test results met product specifications and/or the recommendations in the above referenced guidance document.
Table IX-2 In Vitro Engineering Testing
| Test | Test Description | Results |
| --- | --- | --- |
| Scaffold Dimensional and Functional Testing | | |
| Uniformity of Expansion (UoE) | Determines the uniformity of expansion along the scaffold length following nominal deployment. | PASS |
| Scaffold Percent Length Change | Determines the difference in scaffold length pre-and post-expansion following nominal or post-dilated deployment. | PASS |
| Percent Recoil | Determines the amount of recoil by which the outer diameters of the scaffold decreases from its expanded diameter on the inflated delivery balloon to its relaxed diameter after deflating the balloon following nominal and post-dilated deployment. | PASS |
| Circumferential Radial Strength | Determines the radial force or pressure required to permanently deform the deployed scaffold following nominal and post-dilated deployment. | PASS |
| Radial Stiffness | Determines the radial stiffness of the deployed scaffold following nominal and post-dilated deployment. | For Characterization Only |
| Inner Scaffold Diameter Prior to Strut Fracture / Post-Dilate to Fracture (PDTF) | Determines the limit for expansion before strut fracture. | PASS |
| Maximum Crossing Profile Diameter | Determines the crossing profile / crimped scaffold outer diameter. | PASS |
| Minimum Scaffold Dislodgement Force (Distal) | Determines the minimum force required to dislodge the scaffold from the delivery system in the distal direction. | PASS |
| Minimum Scaffold Dislodgement Force (Proximal) | Determines the minimum force required to dislodge the scaffold from the delivery system in the proximal direction. | PASS |
| Nominal Scaffold ID | Determines the scaffold inner diameter (ID) when the device is inflated to nominal balloon pressure. | PASS |
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Table IX-2 In Vitro Engineering Testing
| Test | Test Description | Results |
| --- | --- | --- |
| Scaffold Markers (Marker Verification) | Verifies the presence of the scaffold markers (marker beads) after subjecting the system to an environment similar to that seen in routine use, including post-dilated deployment. | PASS |
| Visual Inspection / Scaffold Placement | Visually inspects a scaffold and scaffold delivery system and verifies there is no damage to the scaffold and verifies the scaffold placement while in the crimped state. | PASS |
| Pullback into Guiding Catheter | Determines the ability of the un-deployed system to be withdrawn into a guiding catheter. | PASS |
| Scaffold Dimensions (Ring Strut Width and Tube Wall Thickness) | Measures dimension tolerances for the uncoated, as cut, pre-sterile scaffold. | PASS |
| Scaffold Percent Surface Area | Scaffold Percent Surface Area (scaffold-artery ratio) was determined using a theoretical calculation based on the scaffolded vessel area and a 3D computational model of the scaffold design. | For Characterization Only |
| Radiopacity | Evaluated the ability to visualize the Absorb GT1 BVS System using fluoroscopy during scaffold delivery, deployment, and after implementation. | PASS |
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Table IX-2 In Vitro Engineering Testing
| Test | Test Description | Results |
| --- | --- | --- |
| Magnetic Resonance Imaging (MRI) Safety and Compatibility | Non-clinical testing has demonstrated the Absorb GT1 BVS is MR Conditional (as defined in ASTM F2503-13). A patient with this device can be safely scanned in all MR environments 3T or less.
RF-Induced Heating of Tissue around Absorb GT1 BVS
• Experimental data demonstrates that RF-induced heating is minimal. The temperature rise due to RF heating of the Absorb GT1 BVS is similar to that of the background rise with no implant as tested at 1.5T and 3.0T MRI systems per ASTM F2182-11a.
• Scientific Rationale indicates that Absorb GT1 BVS has minimal RF-induced heating based on both temperature rise and energy deposition calculations.
Magnetically Induced Displacement Force
• Experimental data demonstrate that the magnetic force measured per ASTM F2052-14 on the Absorb GT1 BVS is minimal.
• Scientific Rationale indicates that the calculated magnetically induced displacement force on the platinum marker beads is less than its weight in any conceivable (20T) MR system. The marker beads thus meet the safety criterion that magnetic force not exceed the implant weight.
Magnetically Induced Torque
• Experimental data demonstrate that magnetically induced torque on the Absorb GT1 BVS is minimal since force on the Absorb GT1 BVS does not exceed its weight and the Absorb GT1 BVS does not move before and after entering the magnetic field (3T system).
• Scientific Rationale indicates that the calculated worst case torque ratio is 0.256. The torque ratio on the marker beads is less than the gravity value for any conceivable MR system (20T).
Image Artifacts
• Experimental data demonstrate that image artifacts on Absorb GT1 BVS are minimal per ASTM F2119-07 (reapproved 2013). | PASS |
| Scaffold Mechanical Properties | Uniaxial tensile testing was performed to characterize the mechanical properties of PLLA expanded tubing used to manufacture the scaffold. | For Characterization Only |
| Longitudinal Scaffold Compression | Determines the total longitudinal scaffold compression when axially loaded. | For Characterization Only |
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Table IX-2 In Vitro Engineering Testing
| Test | Test Description | Results |
| --- | --- | --- |
| Accelerated Structural Fatigue | Testing conducted to demonstrate structural durability of the scaffold under expected in vivo cyclic loading conditions for an equivalent of 1 year (~40 million cycles) in an overlapped configuration on a static bend with a radius of 15 mm. | PASS |
| Delivery System Dimensional and Functional Testing | | |
| Inner Member Lumen Collapse Pressure | Determines if Inner Member (IM) collapse is reversible at negative pressure after inflation to specified pressures for the scaffold delivery systems. | PASS |
| Balloon Shoulder to Marker Alignment | Determines the distance between the balloon shoulder and marker for the scaffold delivery system. | PASS |
| Minimum Balloon Working Length | Determines the minimum balloon working length measurement of the scaffold delivery system. | PASS |
| Guidewire Lumen Dimensions | Measures the guidewire lumen dimensions for the scaffold delivery system. | PASS |
| Balloon Rated Burst Pressure | Statistically demonstrates with 95% confidence that at least 99.9% of Absorb GT1 BVS Systems will not rupture below the rated burst pressure (RBP). | PASS |
| Maximum Label Compliance Pressure | Statistically demonstrates with 95% confidence that at least 99% of Absorb GT1 BVS Systems will not rupture below the maximum labeled compliance (MLC) pressure. | PASS |
| Balloon Fatigue Resistance | Statistically demonstrates with 95% confidence that at least 90% of Absorb GT1 BVS Systems will sustain 10 repeated inflations to the rated burst pressure. | PASS |
| Balloon Deflation Time | Measures the inflation and deflation time of a balloon from a given pressure. | PASS |
| Catheter Preparation | Determines the number of double negative aspiration procedures necessary to displace air from the balloon with contrast medium. | PASS |
| Catheter Body and Proximal Adaption Pressure Integrity | Determines the pressure at which the catheter shaft inflation lumen and proximal adaption fail for a scaffold delivery. | PASS |
| Catheter Flexibility and Kink | Determines the minimum radius of curvature at which the system fails. | PASS |
| Tip Entry Outer Diameter | Measures the entry profile of the scaffold delivery system catheter tip. | PASS |
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Table IX-2 In Vitro Engineering Testing
| Test | Test Description | Results |
| --- | --- | --- |
| Dimensional Specifications | Measures the dimensions of the scaffold delivery system: • Tip Dimension ○ Tip Length • Mid-Catheter Junction Dimension ○ Notch OD • Shaft Dimensions ○ Distal Shaft OD ○ Proximal Shaft OD • Proximal Shaft Marker Locations ○ Femoral Marker ○ Brachial Marker • Catheter Length ○ Total Catheter Length ○ Distal Catheter Length | PASS |
| Catheter Tensile Strength | Determines the bond strength of a scaffold delivery system at the following locations: Proximal Balloon Seal, Notch Seal / Outer Member to Hypotube Seal, Proximal Adaption, and Soft Tip. | PASS |
| Hydrophilic Coating (Dry Adhesion) | Determines the adhesion of the hydrophilic coating on the scaffold delivery system shaft. | PASS |
| Hydrophilic Coating (Coating Coefficient of Friction) | Determines the kinetic coefficient of friction of hydrophilically-coated shafts of the scaffold delivery system. | PASS |
| Catheter Torque | Determines the rotation number required to break joints and/or materials or to lose functional integrity for the scaffold delivery system. | PASS |
| Hydrophilic Coating Integrity (Visual Inspection) | A visual assessment of the catheter coating integrity on the surface of the catheters before and after simulated use conditioning of a scaffold delivery system. | For Characterization only |
| Delivery, Deployment, and Retraction (DDR) | Confirms that the system is able to safely and reliably deliver the scaffold to the intended location according to the instructions for use, without damage to the scaffold. | PASS |
# A3. Coating Characterization Testing
The coating characterization testing conducted on the Absorb GT1 BVS System is summarized in Table IX-3.
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Table IX-3 Coating Characterization Testing
| Test | Test Description | Results |
| --- | --- | --- |
| Coating Integrity | Determines the percent compromised surface area of the scaffold following post-dilated deployment | PASS |
| Particulate Matter by Tracking Method | Determines the particulate matter generated during simulated tracking and deployment of the scaffold at RBP. | PASS |
| Particulate Matter by Beaker Method | Determines the particulate matter generated during deployment and over expansion of the scaffold in a beaker of water. | For Characterization Only |
| Particulate Matter by Tracking Method (Overlap Configuration) | Determines the particulate matter generated during simulated tracking and deployment of two scaffolds in an overlapped configuration at RBP. | For Characterization Only |
| Accelerated Embolic and Coating Fatigue (Overlap Configuration) | Testing conducted to demonstrate coating durability of the Absorb GT1 BVS System under expected in vivo cyclic loading conditions for an equivalent of 1 year (~40 million cycles) in an overlapped configuration on a static bend with a radius of 15 mm. | For Characterization only |
| Acute Particulate Chemical Characterization | Testing conducted to provide chemical characterization for the particulates generated from the system using the particulate matter by tracking method. | For Characterization only |
| Embolic Fatigue Particulate Chemical Characterization | Testing conducted to provide chemical characterization for the particulates generated from the scaffold during embolic fatigue characterization. | For Characterization only |
| Coating Physical Structure and Chemical Properties | Characterizes various aspects of the coated scaffold, including: • Intra-scaffold coating uniformity • Coating adhesion • Coating thickness • Coating morphology • Coating adhesion after balloon rupture | For Characterization only |
# A4. Chemistry, Manufacturing & Controls (CMC) Testing
Where applicable, International Conference on Harmonisation (ICH) Guidelines were followed for the testing routinely performed on the Absorb GT1 BVS System as part of the finished product release. This testing is summarized in Table IX-4. Information to support the stability of the Absorb GT1 BVS System is summarized separately in Section IX.A5 Stability/Shelf Life.
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Table IX-4 Absorb GT1 BVS System Analytical Release Testing
| Test | Test Description |
| --- | --- |
| Appearance | A visual inspection is conducted to verify that the appearance of the Absorb GT1 BVS System meets the specification established for finished product release. |
| Identity | Assays are conducted to verify the identity of the drug substance, everolimus, on the Absorb GT1 BVS System using two different methods. |
| Total Content | Assay is conducted to quantitatively verify that the total amount of drug on the Absorb GT1 BVS System meets the specification established for finished product release. |
| Content Uniformity | Multiple scaffolds are tested to verify that the uniformity of the drug content between individual scaffolds meets the specification established for finished product release. |
| Degradation Products / Impurities | Assays are conducted to quantitatively verify the amount and type of degradation products / impurities meet the specification established for finished product release. |
| Particulate Matter by Tracking Method | The amount of particulate matter generated during simulated use is verified to meet the specification established for finished product release. |
| USP <85> Bacterial Endotoxins Test | The amount of bacterial endotoxins is verified to meet the specification established for finished product release. |
| In Vitro Drug Release | The in vitro drug release profile of the drug substance, everolimus, is verified to meet the specification established for finished product release. |
| Residual Solvent (Acetone) | The amount of residual solvent, acetone, is verified to meet the specification established for finished product release. |
| Number Average Molecular Weight (Mn) | The number average molecular weight is verified to meet the specification established for finished product release. |
| Sterility | Product is released by verifying that the dose complied with validated sterilization parameters and satisfies the requirement for labeling the finished product as sterile. |
| BHT Content | The amount of BHT is verified to meet the specification established for finished product release. |
# A5. Stability / Shelf Life
A formal stability study was conducted to establish a shelf life / expiration date for the Absorb GT1 BVS System. The stability attributes, including Appearance, Total Content, Degradation Products / Impurities, Particulate Matter by Tracking Method, In Vitro Drug Release, Number Average Molecular Weight $(M_{n})$ , Whole Package Integrity
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Leak Test (bubble test, in lieu of Sterility), and BHT Content were performed at each of the preselected stability time points. Tests for Identification, Content Uniformity, Residual Solvent (Acetone), and Sterility by Dosimetry were performed for initial lot release only and were not monitored during stability. USP <85> Bacterial Endotoxin Test, required for initial lot release only, was also performed every 6 months for the long-term storage condition (25°C/60%RH) of the formal stability study for informational purposes only. Testing to establish container closure integrity was conducted to ensure that sterility was maintained during the shelf life of the product. Functional testing of the Absorb GT1 BVS System was conducted on aged product. The data generated to-date support a shelf life of 12 months for the Absorb GT1 BVS System.
## A6. Sterilization
The Absorb GT1 BVS System is sterilized by means of electron-beam (e-beam) radiation to meet a Sterility Assurance Level (SAL) of 10⁻⁶ in accordance with EN ISO 11137-1:2006 / Amd1:2013, Sterilization of health care products – Radiation – Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices. Pursuant to the validation requirements, the Absorb GT1 BVS System has been successfully qualified for one time e-beam sterilization. In addition, the amount of bacterial endotoxins was verified to be within the specification limits.
## B. Animal Studies
A series of GLP in vivo studies were conducted in the porcine coronary artery model in order (a) to evaluate the in vivo pharmacokinetic profile, (b) to evaluate the in vivo degradation profile, and (c) to demonstrate the in vivo safety of the Absorb GT1 BVS System.
The in vivo testing was conducted in accordance with one or more of the following general regulations, guidance documents, and consensus documents:
- Good Laboratory Practices Regulations (21 CFR § 58)
- Guidance for Industry and FDA Staff: General Considerations for Animal Studies for Cardiovascular Devices CDRH. Rockville, MD, 2010
- Guidance for Industry and FDA Staff: – Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems, 2005
- Schwartz, R. S., et al. "Drug-Eluting Stents in Preclinical Studies: Updated Consensus Recommendations for Preclinical Evaluation." Circ Cardiovasc Intervent 1(2): 143-153, 2008.
- Schwartz, R. S., et al. "Drug-eluting stents in preclinical studies: recommended evaluation from a consensus group." Circulation 106(14): 1867-1873, 2002.
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B1. In Vivo Pharmacokinetics
Three (3) GLP in vivo pharmacokinetics (PK) studies were conducted in porcine coronary arteries in order to determine the in vivo PK profile of everolimus for the Absorb GT1 BVS System. The first of these studies included two (2) PK studies of up to 90 days duration in which consistency in the in vivo pharmacokinetics profiles between Absorb BVS (manufactured in Mountain View) and Absorb BVS (manufactured in Temecula) was demonstrated. The third study included time points up to 300 days and illustrated the complete profile of everolimus elution, and through biostatistical analysis, demonstrated the bioequivalence in drug elution profiles between the Absorb GT1 BVS and the XIENCE V stent, both of which share the same drug dose density of everolimus (100 µg/cm²). Summaries of the in vivo PK studies conducted to support product safety are provided in Table IX-5.
B2. In Vivo Degradation
Three (3) GLP in vivo degradation studies were conducted in porcine coronary arteries in order to determine the in vivo degradation profile for the Absorb GT1 BVS. These studies are inclusive of time points through 42 months, with results demonstrating complete scaffold resorption by approximately 36 months. A summary of the in vivo degradation studies conducted to support product safety is provided in Table IX-5.
B3. In Vivo Safety
Seven (7) GLP in vivo safety studies were conducted in the porcine coronary artery model in order to demonstrate the in vivo safety of the Absorb GT1 BVS. These studies are inclusive of acute (3 days), subchronic (28, 90 days), and chronic (180 days and 12 to 48 months) time points to illustrate the safety of Absorb BVS from implant to beyond complete resorption with multiple interim time points assessed throughout the resorption period. In addition, two (2) of these seven in vivo safety studies were conducted to demonstrate the safety of Absorb GT1 BVS in an overlapping configuration at 28 and 90 days. These studies used XIENCE V (in single and overlapping configurations) as the control article. A summary of the in vivo safety studies conducted to support product safety is provided in Table IX-5.
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Table IX-5 GLP In Vivo PK, Degradation, and Safety Studies Conducted for the Absorb GT1 BVS System
| Study Number (Designation) | Test/Control Articles | Animal Model | Number | Follow-up Duration | Endpoints |
| --- | --- | --- | --- | --- | --- |
| Pharmacokinetics R0100315QWB (PK-90a) | Test: Absorb BVS (mfg MTV) Control: none | Farm swine (n = 3/time point); RCA, LAD, LCX, 1 scaffold per artery with 2-3 scaffolds/ animal | Test: 6-7 scaffolds per time point Control: N/A | 3 hours, 1, 3, 7, 14, 28, 60 and 90 days | Characterization of in vivo pharmacokinetics: drug release, blood and tissue drug concentrations. |
| Pharmacokinetics R0110825QWB (PK-90b) | Test: Absorb BVS (mfg TEM) Control: none | Farm swine (n = 3/time point); RCA, LAD, LCX, 1 scaffold per artery with 2-3 scaffolds/ animal | Test: 7-9 scaffolds per time point Control: N/A | 3 hours, 1, 3, 7, 14, 28, 60 and 90 days | Characterization of in vivo pharmacokinetics: drug release, blood and tissue drug concentrations. |
| Pharmacokinetics R01130812QWB (PK-300) | Test: Absorb BVS (mfg TEM) Control: none | Farm swine and Yucatan mini-swine (n = 3/time point); RCA, LAD, LCX, 1 scaffold per artery with 2-3 scaffolds/ animal | Test: 6-8 scaffolds per time point Control: N/A | 3 hours, 1, 3, 7, 14, 28, 60, 90, 180, and 300 days | Characterization of in vivo pharmacokinetics: drug release, blood and tissue drug concentrations. Bioequivalence in drug release to XIENCE V. |
| Polymer Degradation R0100610JCP (D-28) | Test: Absorb BVS (mfg MTV) Control: none | Farm swine (n = 5); RCA, LAD, LCX, 1 scaffold per artery with 2-3 scaffolds/ animal | Test: 12 scaffolds Control: N/A | 28 days | Characterization of in vivo degradation profile with respect to M_{n}, mass loss, and PDI |
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Table IX-5 GLP In Vivo PK, Degradation, and Safety Studies Conducted for the Absorb GT1 BVS System
| Study Number (Designation) | Test/Control Articles | Animal Model | Number | Follow-up Duration | Endpoints |
| --- | --- | --- | --- | --- | --- |
| Polymer Degradation R0100223JCP (D-90-180) | Test: Absorb BVS (mfg MTV) Control: none | Farm swine (n = 4, 90 days) and Yucatan mini-swine (n = 6, 180 days); RCA, LAD, LCX, 1 scaffold per artery with 2-3 scaffolds/ animal | Test: 12 (90 days), 14 (180 days) scaffolds per time point Control: N/A | 90 and 180 days | Characterization of in vivo degradation profile with respect to M_{n}, mass loss, and PDI |
| Polymer Degradation R0090623JCP (D-12-42) | Test: Absorb BVS (mfg MTV) Control: none | Yucatan mini-swine (n = 3-6 per time point); RCA, LAD, LCX, 1 scaffold per artery with 2-3 scaffolds/ animal | Test: 8 - 12 per time point Control: N/A | 12, 18, 24, 30, 36, and 42 months | Characterization of in vivo degradation profile with respect to M_{n}, mass loss, and PDI |
| Safety R110906JJB (S-28) | Test: Absorb BVS (mfg TEM) Control: XIENCE V | Farm swine (n = 9); RCA, LAD, LCX; 1 device/artery; 1-2 test and 1 control/ animal | Test: 12 Control: 9 | 28 days | • Systemic (morbidity / mortality)
• Quantitative coronary angiography
• Histomorphology
• Endothelialization by SEM
• (Histomorphometry, OCT, IVUS) |
| Safety R110822JJB (S-90) | Test: Absorb BVS (mfg TEM) Control: XIENCE V | Farm swine (n = 10), RCA, LAD, LCX; 1 device/artery; 1-2 test and 1 control/ animal | Test: 14 Control: 10 | 90 days | • Systemic (morbidity / mortality)
• Quantitative coronary angiography
• Histomorphology
• Endothelialization by SEM
• (Histomorphometry, OCT, IVUS) |
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Table IX-5 GLP In Vivo PK, Degradation, and Safety Studies Conducted for the Absorb GT1 BVS System
| Study Number (Designation) | Test/Control Articles | Animal Model | Number | Follow-up Duration | Endpoints |
| --- | --- | --- | --- | --- | --- |
| Safety R110824QWB (S-180) | Test: Absorb BVS (mfg TEM)
Control: XIENCE V | Yucatan mini-swine (n = 9); RCA, LAD, LCX;
1 device/artery; 1-2 test and 1 control/ animal | Test: 12
Control: 9 | 180 days | • Systemic (morbidity / mortality)
• Quantitative coronary angiography
• Histomorphology
• Endothelialization by SEM
• (Histomorphometry, OCT, IVUS) |
| Safety R0100222JCP (S-3-180) | Test: Absorb BVS (mfg MTV)
Control: XIENCE V | Farm swine (n = 7-9, 3, 28, 90 days) and Yucatan mini-swine (n = 9, 180 days);
RCA, LAD, LCX,
1 device per artery; 1-2 test and 1 control/ animal | Test: 12 - 14
Control: 7 - 9 | 3, 28, 90, and 180 days | • Systemic (morbidity / mortality)
• Quantitative coronary angiography
• Histomorphology
• Endothelialization by SEM
• (Histomorphometry, OCT, IVUS) |
| Safety R0090622JCP (S-12-48) | Test: Absorb BVS (mfg MTV)
Control: XIENCE V | Yucatan mini-swine (n = 7-13 per time point);
RCA, LAD, LCX,
1 device per artery; 1-2 test and 1 control/ animal | Test: 12-21
Control: 7-13 | 12, 18, 24, 30, 36, 42, and 48 months | • Systemic (morbidity / mortality)
• Quantitative coronary angiography
• Histomorphology
• Endothelialization by SEM (12 months)
• (Histomorphometry, OCT, IVUS) |
| Overlap Safety R0090326JCP (OL-28) | Test: overlapping Absorb BVS (mfg MTV)
Control: overlapping XIENCE V | Farm swine (n = 8); RCA, LAD, LCX;
1 OL pair per artery; 1-2 OL test pair and 1 OL control pair/ animal | Test: 12 pairs
Control: 8 pairs | 28 days | • Systemic (morbidity / mortality)
• Quantitative coronary angiography
• Histomorphology
• Endothelialization by SEM
• (Histomorphometry, OCT) |
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Table IX-5 GLP In Vivo PK, Degradation, and Safety Studies Conducted for the Absorb GT1 BVS System
| Study Number (Designation) | Test/Control Articles | Animal Model | Number | Follow-up Duration | Endpoints |
| --- | --- | --- | --- | --- | --- |
| Overlap Safety R0090325JCP (OL-90) | Test: overlapping Absorb BVS (mfg MTV)
Control: overlapping XIENCE V | Farm swine (n = 9); RCA, LAD, LCX;
1 OL pair per artery; 1-2 OL test pair and 1 OL control pair/animal | Test: 12 pairs
Control: 9 pairs | 90 days | • Systemic (morbidity / mortality)
• Quantitative coronary angiography
• Histomorphology
• Endothelialization by SEM
• (Histomorphometry, OCT) |
X. SUMMARY OF PRIMARY CLINICAL STUDIES
The applicant performed a pivotal clinical study in the US and Australia under IDE G120002 to establish a reasonable assurance of safety and effectiveness of percutaneous coronary intervention with the Absorb GT1 BVS System for improving coronary luminal diameter in patients with ischemic heart disease due to de novo native coronary artery lesions (length ≤ 24 mm) with a reference vessel diameter of ≥ 2.5 mm and ≤ 3.75 mm. Data from this clinical study, the ABSORB III Randomized Controlled Trial (RCT), were the basis for the PMA approval decision. Safety and effectiveness information for the Absorb GT1 BVS System is also supported by data from the ABSORB Cohort B clinical trial, ABSORB EXTEND clinical trial, ABSORB II RCT, and ABSORB Japan RCT. In this document, these trials are collectively described as the “ABSORB family of clinical trials” or the “ABSORB trials.” These studies evaluated Absorb performance in subjects with ischemic heart disease caused by de novo lesions in native coronary arteries. Major study characteristics are summarized below and listed in Table X-1. Results from the ABSORB III trial are presented in this section (Section X), and results for the supportive clinical trials are presented in Section XI.
The clinical investigations outlined Section X and Section XI were performed on the previous generation Absorb BVS System. The Absorb GT1 BVS has the same mode of expansion, backbone material, scaffold coating, drug density, permanent scaffold markers, and scaffold design as the Absorb BVS. The Absorb GT1 BVS differs from the Absorb BVS only in the scaffold delivery system. The Absorb GT1 scaffold delivery system utilizes the same principle of operation and materials as other Abbott Vascular RX stent / scaffold systems and coronary dilatation catheters.
Based on the identical scaffold present on both the Absorb GT1 BVS System and the Absorb BVS System, performance of the Absorb GT1 BVS can be predicted to be similar to the performance of the Absorb BVS. Within this section, the Absorb BVS and Absorb GT1 BVS System are collectively referred to as “Absorb” and the Absorb BVS and Absorb GT1 BVS are synonymously referred to as the “Absorb scaffold.”
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Table X-1 Overview of ABSORB Family of Clinical Trials
| | ABSORB III RCT | ABSORB Cohort B | ABSORB EXTEND | ABSORB II RCT | ABSORB Japan RCT |
| --- | --- | --- | --- | --- | --- |
| Study Design | Multi-center Randomized (2:1) Single-blinded Active-Control | Multi-center Non-randomized | Multi-center Non-Randomized Continued Assessment | Multi-center Randomized (2:1) Single-blinded Active-Control | Multi-center Randomized (2:1) Single-blinded Active-Control |
| Numbers of Patients | Total: 2008 primary analysis population Absorb: 1322 XIENCE Control: 686 | Total: 101 Absorb Group 1: 45 Group 2: 56 | Total: 812 Absorb | Total: 501 Absorb: 335 XIENCE Control: 166 | Total: 400 Absorb: 266 XIENCE Control: 134 |
| Numbers of Enrolling Sites | 193 sites for the primary analysis population | 12 sites | 58 sites | 46 sites | 38 sites |
| Study Geography | US and AUS | AUS, EU, NZ | AP, EU, CA, BZ | EU, NZ | JN |
| Vessel Size and Lesion Length | RVD: ≥ 2.5 and ≤ 3.75 mm Length: ≤ 24 mm | RVD: 3.0 mm Length: ≤ 14 mm | Dmax≥ 2.0 mm and Dmax≤ 3.3 mm Length: ≤ 28 mm | Dmax≥ 2.25 mm and ≤ 3.8 mm Length: ≤ 48 mm | Dmax≥ 2.5 mm and ≤ 3.75 mm, Length: ≤ 24 mm |
| # of Treated Lesions Allowed | Up to two de novo lesions in different epicardial vessels. No planned overlap allowed | Up to two de novo lesions in different epicardial vessels. No planned overlap allowed | Up to two de novo lesions in different epicardial vessels. Planned overlap allowed. | Up to two de novo lesions in different epicardial vessels. Planned overlap allowed. | Up to two de novo lesions in different epicardial vessels. No planned overlap allowed. |
| Scaffold/Stent Sizes | Diameter: 2.5, 3.0, 3.5 mm Length: 8, 12, 18, 28 mm | Diameter: 3.0 mm Length: 18 mm | Diameter: 2.5, 3.0, 3.5 mm Length: 12, 18, 28 mm | Diameter: 2.5, 3.0, 3.5 mm Length: 12, 18, 28 mm | Diameter: 2.5, 3.0, 3.5 mm Length: 8, 12, 18, 28 mm |
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Table X-1 Overview of ABSORB Family of Clinical Trials
| | ABSORB III RCT | ABSORB Cohort B | ABSORB EXTEND | ABSORB II RCT | ABSORB Japan RCT |
| --- | --- | --- | --- | --- | --- |
| Primary Endpoint(s) | One-year TLF (non-inferiority) | None | None | • Change in Mean Lumen Diameter from pre- to post-nitrate infusion at 3 years (superiority)
• Change in Minimum Lumen Diameter (MLD) from pre- to post-nitrate infusion at 3 years (non-inferiority, reflex to superiority) | One-year TLF (non-inferiority) |
| Major Secondary Endpoints | • Angina at 1 year
• Target Vessel Revascularization at 1 year
• All revascularization at 1 year
• Diabetic subjects at 1 year
• Vasoreactivity at 3 years
• Change in MLA (Mean Lumen Area) at 3 years | None | None | Change in MLA (Mean Lumen Area) at 3 years | • Late loss at 13 months
• Vasoreactivity at 3-years
• Change in MLA (Mean Lumen Area) at 3-years |
| Post Procedure Antiplatelet Therapy | Clopidogrel, prasugrel or ticagrelor 12 months minimum (per site standard). Aspirin for 5 years | Clopidogrel 6 months minimum (per site standard). Aspirin for 5 years. | Clopidogrel, prasugrel or ticagrelor 6 months minimum (per site standard). Aspirin for 3 years | Clopidogrel, prasugrel or ticagrelor 6 months minimum (per site standard). Aspirin for 5 years | Clopidogrel or prasugrel 12 months minimum (per site standard). Aspirin indefinitely. |
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Table X-1 Overview of ABSORB Family of Clinical Trials
| | ABSORB III RCT | ABSORB Cohort B | ABSORB EXTEND | ABSORB II RCT | ABSORB Japan RCT |
| --- | --- | --- | --- | --- | --- |
| Clinical follow-up | 30, 180 days, and annually 1 to 5 years | 30, 180, 270 days, and annually 1 to 5 years | 30, 180 days, and annually 1 to 3 years | 30, 180 days, and annually 1 to 5 years | 30, 180 days, and annually 1 to 5 years |
| Angiographic Follow-up | 3 years* | Group 1: 180 days, 2 years and 5 years (n=45)
Group 2: 1 year, 3 years, and 5 years (n=56) | Post-procedure and 2 years* | 3 years | 13 months, 2 to 4 years* |
| Angiography, IVUS and/or OCT Follow-up | 3 years* | Group 1: 180 days, 2 years and 5 years(n=45)
Group 2: 1 year, 3 years and 5 years (n=56) | Post-procedure and 2 years* | 3 years | 2 to 3 years* |
| PK Study | Yes (12 subjects; US) | None | None | None | None |
| Status | Completed enrollment. Follow-up through 1 year completed. Follow-up through 5 years ongoing. | Completed enrollment and follow-up. | Completed enrollment. Follow-up through 1 year completed. Follow-up through 3 years ongoing. | Completed enrollment. Follow-up through 1 year completed. Follow-up through 5 years ongoing | Completed enrollment. Follow-up through 1 year completed. Follow-up through 5 years ongoing. |
AP, Asia Pacific; AUS, Australia; BZ, Brazil; CA, Canada; EU, Europe; JN, Japan; NZ, New Zealand; US, the United States of America
*Imaging sub-group. Three-year follow-up imaging data are not available to date.
**On a subset of patients that were available for follow-up
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## A. Study Design
The ABSORB III Randomized Controlled Trial (ABSORB III) is a prospective, multicenter study, registering 2,230 subjects. The primary objective of ABSORB III is to evaluate the safety and effectiveness of Absorb compared to 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. The ABSORB III trial includes the following 4 study groups:
### Lead-in Group (24 subjects)
A non-randomized group to evaluate the applicability and transferability of the didactic Absorb physician training plan to United States (US) clinical practice in up to 50 subjects. The registration of the ABSORB Lead-in subjects began on December 28, 2012 and was completed on April 1, 2013. The clinical outcomes in Lead-in subjects do not contribute to the ABSORB III primary endpoint.
### Primary Analysis Group (2,008 subjects)
This is a randomized (2:1 Absorb to XIENCE), single-blind study designed to support US approval of Absorb by showing non-inferiority of Absorb compared to XIENCE in 1-year target lesion failure (TLF). The first randomized subject was treated on March 22, 2013 and the last subject was treated on April 3, 2014. Results from the ABSORB III primary analysis group are presented in this section
### Imaging Cohort (186 subjects)
A randomized (2:1 Absorb to XIENCE) sub-study to evaluate long-term vascular function and patency of Absorb-treated arteries compared to XIENCE-treated arteries. Three-year follow-up imaging data are not available to date.
### Pharmacokinetic (PK) Group (12 subjects)
A prospective, open-label, unblinded sub-study to determine the pharmacokinetics of everolimus delivered by Absorb in subjects who only receive Absorb with a maximum of two de novo native coronary artery lesions after implantation of Absorb. The clinical outcomes in PK subjects do not contribute to the ABSORB III primary endpoint. The first PK subject was treated on June 2, 2014 and the subject was treated on September 17, 2014. Results from the pharmacokinetic analysis can be found in Section X.D4 – Pharmacokinetics – ABSORB III PK.
### ABSORB IV Randomized Controlled Trial
ABSORB IV is a prospective randomized controlled trial (RCT) that began enrollment after completion of the enrollment of the ABSORB III trial primary analysis subject
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cohort. ABSORB IV will enroll 3,000 subjects, randomized 1:1 to the BVS or the XIENCE stent. The study inclusion and exclusion criteria are generally similar to ABSORB III. A landmark analysis will pool ABSORB IV subjects with the 2,008 subjects from the ABSORB III primary analysis group. As of February 2016, 1,498 ABSORB IV subjects have been randomized. Enrollment is expected to be complete in December 2016.
The database for this PMA reflect data collected through April 2, 2015 and includes 2008 Primary Analysis Group patients and 12 PK Group patients. There were 193 investigational sites. The control group was the XIENCE family of products, an approved drug-eluting stent (DES) with similar indications for use.
The ABSORB III trial is powered for the primary endpoint of target lesion failure (TLF) at 1-year, a composite endpoint of cardiac death, myocardial infarction attributable to target vessel (TV-MI) or ischemia-driven target lesion revascularization (ID-TLR). The results presented in this clinical section are based on the ITT population, defined as subjects registered in the study at the point of randomization, regardless of the treatment actually received. ITT subjects are analyzed in the treatment group to which they were randomized.
The primary endpoint was TLF at 1 year was also evaluated in the pre-specified Per-Treatment Evaluable (PTE) population, defined as subjects with no major protocol deviations treated with only Absorb or XIENCE at the target lesion, with the analysis based on the treatment (Absorb or XIENCE) actually received.
The primary endpoint of TLF at 1 year is evaluated using the difference in event rates. The hypothesis test is designed to show non-inferiority of Absorb to XIENCE for the primary endpoint with a one-sided alpha of 0.025. The null (H₀) and alternative (Hₐ) hypotheses are:
H₀: TLFᵃbsorb - TLFᵃXIENCE ≥ ΔⁿE
Hₐ: TLFᵃbsorb - TLFᵃXIENCE < ΔⁿE
TLFᵃbsorb and TLFᵃXIENCE are the 1-year TLF rates in the Absorb and XIENCE arms, respectively. ΔⁿE is the non-inferiority margin (4.5%).
The likelihood score method by Farrington and Manning is performed for the NI test. A successful trial requires a p-value less than 0.025 from this NI test.
Oversight for the ABSORB III trial includes an angiographic core laboratory, clinical events committee (CEC) and data safety monitoring board (DSMB). The angiographic core laboratory was responsible for reviewing all available follow-up coronary angiograms for registered subjects, to determine if a revascularization was performed by PCI, and if so, whether or not the revascularization was related to the target lesion, the target vessel or a non-target vessel. The data from the angiographic core laboratory was provided to CEC for adjudication of stent thrombosis events. The CEC was responsible
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for adjudicating specified clinical endpoints based on the specific criteria used for the categorization of clinical events. The DSMB served in an advisory role to Abbott Vascular by reviewing cumulative data from the clinical trial at prescribed intervals for the purpose of safeguarding the interests of trial participants.
1. Clinical Inclusion and Exclusion Criteria
Enrollment in the ABSORB III study was limited to patients who met the following inclusion criteria:
Subjects at least 18 years old and suitable for PCI with symptomatic myocardial ischemia with a maximum of two de novo native coronary artery lesions in separate epicardial vessels.
Key angiographic inclusion criteria included: lesion located in native coronary artery with reference vessel diameter (RVD) ≥ 2.5 mm and ≤ 3.75 mm by visual estimation and lesion length of ≤ 24 mm by visual estimation; visually estimated or quantitatively assessed % diameter stenosis (DS) of ≥ 50%; and TIMI flow ≥ 1.
Patients were not permitted to enroll in the ABSORB III study if they met any of the following exclusion criteria:
Lesion in left main or aorto-ostial RCA lesion (within 3 mm of ostium); excessive tortuosity (≥ two 45° angles) proximal to or within the target lesion; extreme angulation (≥ 90°) proximal to or within the target lesion; moderate or heavy calcification proximal to or within the target lesion; target vessel containing thrombus; lesion involving a bifurcation with side branch ≥ 2 mm in diameter, or side branch with either an ostial or non-ostial lesion with diameter stenosis > 50%, or a side branch requiring dilatation.
2. Follow-up Schedule
All patients were scheduled to return for follow-up examinations at 30 ± 7 days; 180 ± 28 days; 1 year ± 28 days; 2 years ± 28 days; 3 years ± 28 days; 4 years ± 28 days; and 5 years ± 28 days post-procedure. Office visit and ECG were required for the 1-year follow-up. All other follow-up are either office visit or telephone contact.
Pre-procedure, subjects were required to receive a loading dose of ≥ 300 mg of aspirin within 24 hours prior to index procedure, regardless of whether the patient was previously taking aspirin. Subjects were also required to receive a loading dose of a P₂Y₁₂ receptor antagonist within 24 hours prior to index procedure (preferred), but in all cases no greater than 1 hour after the end of the procedure. Subjects were required to receive dual antiplatelet therapy for 1 year after the index procedure. Post-procedure, the objective parameters measured during the study are presented in Table X-2 below. Adverse events and complications were recorded at all visits.
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Table X-2 ABSORB III Schedule of Events
| PROCEDURE/TEST | Baseline | Baseline (within 7 days) | Pre-Procedure (within 24 hours) | Procedure | Post-Procedure | 30 days (± 7 d) Telephone contact or office visit | 180 days (± 28 d) Telephone contact or office visit | 1 yr (± 28 d) office visit | 2, 3, 4, 5 yrs (± 28 d) Telephone contact or office visit | Unscheduled visits |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Subject Medical/Clinical History (Age, Sex, Risk Factors, Angina Status, Cardiac History) | ✓ | | | | | | | | | |
| Subject Informed Consent (Must be obtained prior to any study related testing or procedures) | ✓ | | | | | | | | | |
| General Inclusion/Exclusion Criteria | ✓ | | | | | | | | | |
| Angiographic Inclusion/Exclusion Criteria | | | | ✓7 | | | | | | |
| Pregnancy Test (if applicable) | | ✓ | | | | | | | | |
| Hgb, Platelet Count, Creatinine, HbA1c, eGFR, WBC | ✓1 | | | | | | | | | |
| CK and CK-MB | | | ✓2 | | ✓3 | | | | | ✓6 |
| Troponin I or T | | | | | | | | | | ✓6 |
| ECG | | | ✓2 | | ✓4 | | | ✓ | ✓8 | ✓6 |
| Coronary Angiogram, IVUS or OCT | | | | ✓7 | | | | | ✓8 | |
| Study device information | | | | ✓ | | | | | | |
| Per Protocol Medications5 | | | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ |
| Concomitant Medications | ✓ | | | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ |
| Adverse Events | | | | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ |
| Patient Reported Outcome Instruments9 | ✓10 | | | | | ✓ | | ✓ | ✓ | |
| 1. The 21 day labs should be known prior to index procedure. HbA1c is to be collected in diabetic subjects only, and its result is not needed prior to the index procedure.2. Within 48 hours pre-procedure will be acceptable except when there is evidence of acute or recent | | | | | | | | | | |
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(<7 days) myocardial infarction or unstable angina prior to the procedure, in which case pre-procedure draws/assessments must be within 24 hours. For ECGs, 12-lead must be used. If the subject does not have a known diagnosis of AMI or unstable angina within 96 hours prior to the index procedure, assessment of cardiac enzymes may be obtained after the start of the index procedure but prior to device implantation.
3. Three draws required: 1) Pre-procedure (prior to stent deployment); 2) 6-12 hours post-procedure; 3) 18-24 hours post-procedure or at the time of discharge as long as discharge is at or after 16 hours post-procedure (for hospitals required to discharge stable subjects prior to 16 hours, the subject may be discharged but will have to return to the enrolling institution for their second biomarker draw). If either of the post-procedure CK-MB levels are $\geq 3\mathrm{x}$ ULN, serial CK and CK-MB levels must be drawn until they are falling.
4. ECG must be done between 30-90 minutes post-index procedure.
5. Prasugrel 5 or $10\mathrm{mg}$ daily, clopidogrel a minimum of $75\mathrm{mg}$ daily or ticagrelor $90\mathrm{mg}$ twice daily, must be given for a minimum of 12 months, and Aspirin $\geq 75\mathrm{mg}$ to $\leq 100\mathrm{mg}$ daily must be taken through 5 years follow up during the study, and should continue to be taken indefinitely. If a subject develops hypersensitivity to clopidogrel, prasugrel or ticagrelor, subject may be switched to ticlopidine at a dose in accordance with standard hospital practice.
6. Cardiac enzymes CK and CK-MB must be collected and ECG must be done. Troponin measurement is per site standard.
7. Baseline (prior to pre-dilatation) and final (after stenting/post dilatation) angiogram must be obtained and sent to the core laboratory. For imaging sites enrolling an imaging subject, if vessel sizing is conducted using IVUS, OCT or on-line QCA, these images must also be sent to their respective core laboratory. For subjects in imaging study group, post-implantation angiogram and IVUS, or angiogram and OCT will be conducted and images sent to their respective core laboratory. Images will be sent to respective core laboratory.
8. Subjects in the imaging study group will receive either at 3 years an angiogram, ECG, plus IVUS or OCT.
9. Patient Reported Outcome instruments (EQ-5D, SAQ, RDS, GAD-7) will be administered to the 2000 primary analysis subjects in ABSORB III only.
10. Every effort should be made to have subjects complete all four patient reported outcomes questionnaires prior to the procedure. However, in situations where this is absolutely not possible, subjects may complete them post-procedure, prior to discharge. Subjects who complete their questionnaires post-procedure should base their responses on their condition prior to the procedure.
## 3. Clinical Endpoints
The ABSORB III primary endpoint was TLF at 1 year, defined as the composite of: cardiac death, myocardial infarction attributable to target vessel (TV-MI), or ischemia-driven target lesion revascularization (ID-TLR), tested for non-inferiority of the BVS vs. XIENCE.
Powered secondary endpoints (tested for superiority of the BVS vs. XIENCE) were:
- Angina at 1 year
- All revascularizations at 1 year
- Ischemia-driven target vessel revascularization (ID-TVR) at 1 year
Other secondary endpoints to examine the safety and effectiveness of Absorb are listed below.
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Components of composite endpoints:
- Death (cardiac, vascular, non-vascular)
- Myocardial infarction attributable to target vessel (TV-MI) or not attributable to target vessel (NTV-MI)
- Ischemia-driven or non-ischemia-driven TLR (ID-TLR, NID-TLR)
- Target vessel revascularization (ID-TVR, non ID-TVR)
Other composite Endpoints:
- Death/All MI
- Cardiac death/All MI
- Cardiac death/All MI/ID-TLR (MACE)
- Cardiac death/All MI/ID-TLR/ID-TVR, non TL (Target Vessel Failure, TVF)
- Death/All MI/All revascularization
Scaffold / Stent Thrombosis (per ARC Definition):
- Timing (acute, sub-acute, late and very late)
- Evidence (definite and probable)
## B. Accountability of PMA Cohort
In ABSORB III, a total of 2008 (Absorb: 1322; XIENCE: 686) patients were randomized at 193 study sites, between March 22, 2013 and April 3, 2014. A total of 1385 lesions were treated in the Absorb arm, and 713 in the XIENCE arm. At the time of the database lock, of the 2008 patients enrolled in the PMA study, 99% (1990) of patients were available at the completion of the study, the 1-year post-index procedure visit: 99.3% (1313) of patients were available in the Absorb arm, and 98.7% (677) in the XIENCE arm. Early termination evaluated at 365 days, due to lost to follow-up, consent withdrawal or death, affected 1.7% (23/1322) of the subjects in the Absorb arm and 1.6% (11/686) in the XIENCE arm. All subjects have completed their 1-year follow-up and clinical follow-up through 5 years is ongoing.
Flow charts summarizing patient accountability for the ITT population, as well as the As-Treated (AT) and Per-Treatment Evaluable (PTE) populations are presented below.
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Subject Flow and 1-year follow-up in ITT population
One-year follow-up includes a window of $\pm 28$ days.
*Includes 11 subjects who received assigned study device in one lesion but did not receive assigned study device in a second lesion.
**A total of 1312 subjects in the Absorb BVS arm completed 1-year follow-up. However, terminated subjects are included in the ITT (intent-to-treat) analysis population for the 1-year primary endpoint of target lesion failure if they die or have a myocardial infarction or a revascularization event prior to termination. One of the 10 terminated subjects in the Absorb BVS arm fell into this category; thus, there were only 9 Absorb BVS subjects excluded from the analysis, resulting in an actual ITT population of $n = 1313$ in the Absorb BVS arm.
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Subject Flow and 1-year follow-up in As-Treated population
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# Subject Flow and 1-year follow-up in the PTE population
## PTE Exclusion Criteria Categorizations
1. Excluded due to angiographic inclusion/exclusion PD
2. Excluded due to general inclusion/exclusion PD
3. Excluded due to treatment strategy PD
## C. Study Population Demographics and Baseline Parameters
The demographics of the study population are typical for a PCI study performed in the US.
The key baseline demographic features and risk factors for the ABSORB III ITT population are shown in Table X-3. All baseline characteristics were balanced with no statistical differences between the study arms. The mean age was $63.5 \pm 10.6$ years in the Absorb arm and $63.6 \pm 10.3$ years in the XIENCE arm. Risk factors having a high prevalence in Absorb and XIENCE arms included hypertension requiring medication
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(81.0% (1071/1322) and 80.6% (553/686), respectively) and dyslipidemia requiring medication (76.3% (1009/1322) and 77.7% (533/686), respectively). All diabetes mellitus comprised 31.5% (416/1320) and 32.7% (224/686), respectively, and insulin-required diabetes mellitus subjects comprised 10.5% (138/1320) and 11.2% (77/686), respectively. For cardiac status, the most common disease presentation in Absorb and XIENCE arms was stable angina (57.3% (757/1321) and 60.8% (417/686), respectively). Subjects with a single diseased artery were most prevalent in the ABSORB III population (69.5% (919/1322) and 67.2% (461/686), respectively).
The mean reference vessel diameter was $2.67 \pm 0.45 \mathrm{~mm}$ and $2.65 \pm 0.46 \mathrm{~mm}$ in the Absorb and XIENCE groups, respectively. The mean lesion length was $12.6 \pm 5.4 \mathrm{~mm}$ and $13.1 \pm 5.8 \mathrm{~mm}$ in the Absorb and XIENCE groups, respectively. The mean diameter stenosis was $65.3\%$ and $65.9\%$ in the Absorb and XIENCE groups, respectively.
Table X-3 ABSORB III Key Baseline Patient Characteristics and Risk Factors - Per-Subject Analysis (Primary Analysis Group, Intent-To-Treat Population)
| | Absorb (N=1322) | XIENCE (N=686) | Difference [95% CI]1 |
| --- | --- | --- | --- |
| Subject Background | | | |
| Age (year) | 63.5 ± 10.6 (1322) | 63.6 ± 10.3 (686) | -0.2 [-1.1, 0.8] |
| Male Subjects | 70.7% (934/1322) | 70.1% (481/686) | 0.53% [-3.62%, 4.80%] |
| Ethnicity – Hispanic or Latino | 3.8% (50/1322) | 3.4% (23/686) | 0.43% [-1.43%, 2.04%] |
| Race2 | | | |
| American Indian or Alaskan Native | 0.6% (8/1322) | 0.3% (2/686) | 0.31% [-0.51%, 0.94%] |
| Asian | 1.5% (20/1322) | 1.9% (13/686) | -0.38% [-1.81%, 0.75%] |
| Black or African Heritage | 5.3% (70/1322) | 5.0% (34/686) | 0.34% [-1.84%, 2.27%] |
| Native Hawaiian or Pacific Islander | 0.6% (8/1322) | 0.1% (1/686) | 0.46% [-0.28%, 1.06%] |
| White | 87.1% (1152/1322) | 88.3% (606/686) | -1.20% [-4.11%, 1.92%] |
| Body Mass Index (kg/m2) | 30.58 ± 6.22 (1322) | 30.47 ± 6.26 (686) | 0.11 [-0.47, 0.69] |
| Current Tobacco Use | 21.3% (281/1322) | 20.7% (142/686) | 0.56% [-3.28%, 4.22%] |
| Any Diabetes Mellitus (DM) | 31.5% (416/1320) | 32.7% (224/686) | -1.14% [-5.49%, 3.12%] |
| DM req. Med. | 28.2% (372/1320) | 28.4% (195/686) | -0.24% [-4.46%, 3.85%] |
| DM req. Insulin | 10.5% (138/1320) | 11.2% (77/686) | -0.77% [-3.77%, 2.01%] |
| HbA1c (%) (All Diabetes Mellitus) | 7.56 ± 1.76 (389) | 7.78 ± 2.06 (209) | -0.22 [-0.55, 0.11] |
| Hypertension req. Med. | 81.0% (1071/1322) | 80.6% (553/686) | 0.40% [-3.15%, 4.12%] |
| Dyslipidemia req. Med. | 76.3% (1009/1322) | 77.7% (533/686) | -1.37% [-5.16%, 2.57%] |
| Prior Coronary Intervention | 38.7% (512/1322) | 38.0% (260/684) | 0.72% [-3.79%, 5.16%] |
| Prior MI | 21.5% (282/1311) | 22.0% (150/681) | -0.52% [-4.42%, 3.23%] |
| Cardiac Status | | | |
| AMI | 2.8% (37/1321) | 2.6% (18/686) | 0.18% [-1.49%, 1.59%] |
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| | Absorb | XIENCE | Difference |
| --- | --- | --- | --- |
| Unstable Angina | 26.9% (355/1321) | 24.5% (168/686) | 2.38% [-1.70%, 6.31%] |
| Stable Angina | 57.3% (757/1321) | 60.8% (417/686) | -3.48% [-7.96%, 1.07%] |
| Silent Ischemia | 10.0% (132/1321) | 10.2% (70/686) | -0.21% [-3.12%, 2.47%] |
| No Current Evidence of Ischemia | 2.1% (28/1321) | 1.3% (9/686) | 0.81% [-0.52%, 1.92%] |
| Single diseased artery | 69.5% (919/1322) | 67.2% (461/686) | 2.31% [-1.93%, 6.65%] |
| Two diseased arteries | 24.3% (321/1322) | 26.4% (181/686) | -2.10% [-6.19%, 1.85%] |
| Three or more diseased arteries | 6.2% (82/1322) | 6.4% (44/686) | -0.21% [-2.61%, 1.94%] |
By normal approximation for continuous variables and Newcombe score method for binary variables.
2Subject can be counted in more than one category
# D. Safety and Effectiveness Results
The primary endpoint of TLF at 1 year was in the ITT population was met and is shown below in Table X-4. The TLF rate at 1 year was $7.8\%$ (102/1313) in the Absorb arm and $6.1\%$ (41/677) in the XIENCE arm. The difference between the two treatment arms was $1.71\%$ with the upper bound of the $95\%$ confidence interval being $3.93\%$ , which was less than the non-inferiority margin of $4.5\%$ . The Absorb arm was non-inferior to XIENCE with a non-inferiority p-value of 0.0070 for observed TLF rates at 1 year.
Table X-4 ABSORB III Primary Endpoint Analysis (Primary Analysis Group - Intent-to-Treat Population, Per-Protocol MI Definition)
| | Absorb (N=1322) | XIENCE (N=686) | Difference (95% CI1) | Non-Inferiority P-Value2 |
| --- | --- | --- | --- | --- |
| 1-Year TLF (Cardiac Death Target Vessel MI, ID-TLR3) | 7.8% (102/1313) | 6.1% (41/677) | 1.71% (-0.51%, 3.93%) | 0.0070 |
Two-sided $95\%$ confidence interval by Farrington-Manning method
2One-sided p-value by using Farrington-Manning non-inferiority test statistic with non-inferiority margin of $4.5\%$ , to be compared with a one-sided significance level of 0.025
3Ischemia-driven target lesion revascularization
Note: 1-year timeframe includes a window of $\pm 28$ days
Note: N is the total number of subjects
Note: MI is per protocol definition: Non Q-wave MI is defined as CK-MB $>5\mathrm{X}$ ULN for peri-procedural MI ( $\leq 48$ hrs post-PCI); CK-MB or Troponin $>$ ULN plus evidence of ischemia for spontaneous MI; Q-wave MI defined as development of new, pathological Q wave on the ECG
For the PTE population, the TLF rate at 1 year was $7.8\%$ (91/1174) in the Absorb arm and $5.7\%$ (38/670) in the XIENCE arm. The difference between the two treatment arms was $2.08\%$ with the upper bound of the $95\%$ confidence interval being $4.35\%$ , which was less than the non-inferiority margin of $4.5\%$ . The Absorb arm was non-inferior to XIENCE regarding the primary endpoint TLF rate at 1 year in the PTE population $(p = 0.0183)$ .
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The analyses of Angina, All Revascularization, and ID-TVR at 1 year for the ITT population are shown in Table X-5. Superiority was not met for any of the powered secondary endpoints with prespecified hypothesis tests. The Angina rate at 1 year was 18.3% (238/1303) in the Absorb arm and 18.4% (125/678) in the XIENCE arm (p = 0.9256). The All Revascularization rate at 1 year was 9.1% (120/1313) in the Absorb arm and 8.1% (55/677) in the XIENCE arm. The ID-TVR rate at 1 year was 5.0% (66/1313) in the Absorb arm and 3.7% (25/677) in the XIENCE arm.
Table X-5 ABSORB-III Powered Secondary Endpoints (Primary Analysis Group - Intent-to-Treat Population)
| Powered Secondary Endpoints | Absorb (N=1322) | XIENCE (N=686) | Difference [95% CL]4 | Superiority P-Value5 |
| --- | --- | --- | --- | --- |
| 1-Year Angina1 | 18.3% (238/1303) | 18.4% (125/678) | -0.17% [-3.77%, 3.42%] | 0.9256 |
| 1-Year All Revascularization2 | 9.1% (120/1313) | 8.1% (55/677) | 1.02% [-1.57%, 3.60%] | N/A6 |
| 1-Year ID-TVR3 | 5.0% (66/1313) | 3.7% (25/677) | 1.33% [-0.51%, 3.18%] | N/A6 |
1First reported angina post discharge (excluding angina following the index procedure through discharge, not to exceed a period of 7 days).
2Includes TLR, TVR non TLR, and non TVR
3Ischemia driven target vessel revascularization
4Without multiplicity adjustment. For Angina at 1 year, Pearson's Chi-square two-sided 95% confidence interval. For All Revascularization and ID-TVR at 1 year, exact two-sided 95% confidence interval.
5Compared with a two-sided significance level of 0.05. For Angina at 1 year, two-sided p-value using Pearson's Chi-square test statistic. For All Revascularization and ID-TVR at 1 year, two-sided p-value using Fisher's exact test statistic.
6According to the pre-specified testing sequence, further testing sto…
