1. BRS Next Large Trials: What is on the Horizon?
Gregg W. Stone MD
Columbia University Medical Center
The Cardiovascular Research Foundation

2. Disclosure Statement of Financial Interest
Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.
Affiliation/Financial Relationship
Company
Absorb global program chair (uncompensated)
Consulting Fees/Honoraria
Abbott
Reva

3. Outstanding Issues with Absorb Bioresorbable Scaffolds
Can adverse event rates be lowered with improved technique?
Are early BVS outcomes acceptable in high-risk pts and complex lesion?
Does Absorb reduce long-term event rates compared to metallic DES?

4. These Questions are Being Addressed by 3 Ongoing Large Absorb Trials
ABSORB IV
AIDA
COMPARE ABSORB

5. Demonstrate very late superiority of Absorb BVS compared to Xience EES
ABSORB III + IV
A clinical program consisting of integrated randomized trials designed to:
Demonstrate noninferiority of Absorb BVS compared to Xience EES at 1 year, resulting in US approval
and
Demonstrate very late superiority of Absorb BVS compared to Xience EES

6. ABSORB III + IV Clinical Trial Program
2,250 pts with up to 2 de novo lesions in different epicardial vessels enrolled, with follow-up for at least 5 years, at up to 122 US and non-US sites
2,000 pts randomized 2:1 ABSORB v XIENCE (+50 lead-in pts and 200 pt non-randomized angio/IVUS/OCT/VM FU cohort)
RVD: mm; Lesion length: ≤24 mm
Scaffold diameters: 2.5, 3.0 and 3.5 mm Scaffold lengths: 12, 18, and 28 mm
Primary endpoint (n=2,000): TLF at 1 year (powered for noninferiority) – US approval
Key question – will it support pricing and reimbursement in our markets of interest?
PIs: SG Ellis, DJ Kereiakes
Study chairman: GW Stone

7. ABSORB III + IV Clinical Trial Program Co-PIs: SG Ellis, DJ Kereiakes
ABSORB IV
~3,000 pts randomized 1:1 ABSORB v XIENCE
RVD: mm; Lesion length: ≤24 mm
Scaffold diameters: 2.5, 3.0 and 3.5 mm Scaffold lengths: 12, 18, and 28 mm
~5,000 total pts (ABSORB III + IV) with up to 3 de novo lesions randomized, with FU for at least 5 years, at up to 130 sites. Blinded between 1-5 years.
Primary endpoints:
1. TLF at 1 year (ABSORB IV pts only) - noninferiority
2. TLF between 1 and 5 years (ABSORB III + IV) - superiority
Key question – will it support pricing and reimbursement in our markets of interest?
PI: GW Stone
Co-PIs: SG Ellis, DJ Kereiakes

8. Differences between ABSORB IV and ABSORB III
ABSORB IV: 3000 pts, rand 1:1 BVS to Xience (vs 2000, 2:1)
ABSORB IV: Enrolling higher-risk and more complex pts
Troponin+ NSTEMI or recent STEMI
Thrombus-containing lesions
Up to 3 de novo lesions (up to 2 in one vessel)
ABSORB IV: Rigorous blinding to enable angina assessment
ABSORB IV: Actively training sites to avoid very small vessel enrollment (RVD <2.5 mm), and near-real time core lab QCA of RVD – sites placed on hold for <2.25 mm and re-trained
ABSORB IV: Strongly recommending 1:1 pre-dilatation and high pressure post-dilatation, both with NC balloons

9. Unique Aspects of ABSORB IV (i)
Blinding measures
Headphones in cath lab
Device allocation not recorded in chart or bills
Blinded FU physicians, nurses and RCs

10. Unique Aspects of ABSORB IV (ii)
Angina assessment
Detailed 5 page angina eCRF (at 1, 3, 6, 9, 12 months, and then yearly through 5 years)
Angina primary endpoint: Adjudicated by a blinded clinical events committee (CEC) from the eCRF and source docs
Perception questionnaire and subgroup analysis
QCA assessment of incomplete revascularization and its relationship to angina

11. Blinded, Pooled, Interim ABSORB IV Outcomes: Comparison to ABSORB III
ABSORB III: 2008 pts randomized 2:1 BVS:EES (1322:686)
ABSORB IV: 3000 pts being randomized 1:1 BVS:EES
ABSORB III Pooled
(N=2008)
(N=2008)1
ABSORB IV Pooled
(N=2494)2,3
QCA RVD <2.25 mm
19%
Post-dilatation (BVS)
66%
Pooled stent/scaffold thrombosis
30 days
1.0%
0.9%
1 year
1.3%
1.1%
Assuming the same event rate for each arm in ABSORB III, but with a 1:1 randomization ratio.
Based on January 16, 2016 data cut (N=2349 with 30 day FU and N=1297 with 1 year FU).
A-IV includes 25% non A-III like subjects (troponin+ NSTEMI/STEMI, 3 lesions treated, and planned staged procedures). 11

12. Blinded, Pooled, Interim ABSORB IV Outcomes: Comparison to ABSORB III
ABSORB III: 2008 pts randomized 2:1 BVS:EES (1322:686)
ABSORB IV: 3000 pts being randomized 1:1 BVS:EES
ABSORB III Pooled
(N=2008)
(N=2008)1
ABSORB IV Pooled
(N=2494)2,3
QCA RVD <2.25 mm
19% 4%
Post-dilatation (BVS)
66%
83%
Pooled stent/scaffold thrombosis
30 days
1.0%
0.9%
1 year
1.3%
1.1%
Assuming the same event rate for each arm in ABSORB III, but with a 1:1 randomization ratio.
Based on January 16, 2016 data cut (N=2349 with 30 day FU and N=1297 with 1 year FU).
A-IV includes 25% non A-III like subjects (troponin+ NSTEMI/STEMI, 3 lesions treated, and planned staged procedures). 12

13. Blinded, Pooled, Interim ABSORB IV Outcomes: Comparison to ABSORB III
ABSORB III: 2008 pts randomized 2:1 BVS:EES (1322:686)
ABSORB IV: 3000 pts being randomized 1:1 BVS:EES
ABSORB III Pooled
(N=2008)
(N=2008)1
ABSORB IV Pooled
(N=2494)2,3
QCA RVD <2.25 mm
19% 4%
Post-dilatation (BVS)
66%
83%
Pooled stent/scaffold thrombosis
30 days
1.0%
0.9%
0.3%
1 year
1.3%
1.1%
0.5%
Assuming the same event rate for each arm in ABSORB III, but with a 1:1 randomization ratio.
Based on January 16, 2016 data cut (N=2349 with 30 day FU and N=1297 with 1 year FU).
A-IV includes 25% non A-III like subjects (troponin+ NSTEMI/STEMI, 3 lesions treated, and planned staged procedures). 13

14. Protocol revisions (sponsor and study leadership blinded)
ABSORB III + IV
Protocol revisions (sponsor and study leadership blinded)
Primary ABSORB III+IV superiority hypothesis changed to assess difference between Absorb and Xience between 3 and 7 to 10 years
ABSORB III: Unblinded between 1 and 3 yrs
ABSORB IV: Primary non-inferiority hypothesis changed to 30 days
ABSORB IV: Unblinded between 30 days and 3 yrs

15. ABSORB IV: 2,553 pts enrolled at 128 sites
ABSORB III + IV
Status Update
ABSORB III: year results will be reported at ACC 2017 as a late breaking trial
ABSORB IV: ,553 pts enrolled at 128 sites

16. AIDA
Amsterdam Investigator–initiateD Absorb strategy ll-comers trial
Clinicaltrials.gov NCT
Start date: August 2013
2,690 “all-comer on label” pts randomized single-blind 1:1 Absorb v Xience
RVD: 2.50 – 4.0 mm; Lesion length: ≤70 mm
Main exclusion criteria: RVD <2.5 mm or >4.0 mm, length >70 mm, unsuccessful pre-dilatation, 2-device bifurcations, ISR
Primary endpoint (noninferiority): TVF at 2 years (cardiac death, TV-NI or TVR)
Key question – will it support pricing and reimbursement in our markets of interest?
PIs: Jan Piek, Robbert de Winter, José Henriques
Study director: Joanna Wykrzykowska

17. Clinicaltrials.gov NCT02486068, Start date: Sept. 2015
Compare Absorb
ABSORB Bioresorbable Scaffold vs. Xience Metallic Stent for Prevention of Restenosis in Patients at High Risk of Restenosis
Clinicaltrials.gov NCT , Start date: Sept. 2015
2,100 “high-risk for restenosis” pts randomized single-blind 1:1 Absorb v Xience
Inclusion criteria: Diabetes; or MVD requiring treatment; or single vessel disease lesions with RVD mm, length >28 mm, CTO, or bifurcation (single stent provisional strategy)
Main exclusion criteria: age >80 years, GFR <45 ml/min, RVD <2.25 mm or >4.0 mm, 2-device bifurcations, ISR, SVG, LM, ostial
Primary endpoint (noninferiority): TLF at 1 year (cardiac death, TV-NI or CI-TLR)
Key question – will it support pricing and reimbursement in our markets of interest?
PI: Peter Smits