1. Study Designs of Short DAPT in the USA – Challenges and Execution of Pivotal Trials
Hans-Peter Stoll, M.D.
Chief Medical Officer Biosensors International
FDA Town Hall
Evaluating DES for High-Risk DAPT Patients
21 February 2017

2. Disclosure Statement:
Hans-Peter Stoll, M.D.
 I am a full-time employee of Biosensors International Group

3. DAPT in the USA – Current Standard of Care
2. The duration of P2Y12 inhibitor therapy after stent
implantation should generally be as follows:
a. In patients receiving a stent (BMS or DES) during
PCI for ACS, P2Y12 inhibitor therapy should
be given for at least 12 months. Options include
clopidogrel 75 mg daily,570 prasugrel 10 mg
daily,567 and ticagrelor 90 mg twice daily.568
(Level of Evidence: B)
b. In patients receiving DES for a non-ACS indication,
clopidogrel 75 mg daily should be given for
at least 12 months if the patient is not at high risk
of bleeding.208,212,571 (Level of Evidence: B)
c. In patients receiving BMS for a non-ACS indication,
clopidogrel should be given for a minimum
of 1 month and ideally up to 12 months (unless the
patient is at increased risk of bleeding; then it
should be given for a minimum of 2 weeks).572
Recommended
DAPT duration:
Any Stent for ACS: ≥ 12 Mo
Longer DAPT protects against ischemic events but increases bleeding risk
DES for non-
ACS: ≥12 Mo
..if not HBR
Open Questions:
Do stents with a biodegradable or no polymer make a difference?
How should patients at high bleeding risk (HBR) be treated?
BMS for non- ACS: ≥1 Mo
Level of Evidence: B

4. Short DAPT – What are the Clinical Issues ?
For which clinical indication ?
How short?
3 months (vs. 12 or 36)
30 days (DES vs BMS)
DAPT termination vs DAPT holiday ?
Clinical outcomes:
Bleeding risk?
Clotting (ST) risk?
Which subgroups ?
Cost?

5. Benefit / Risk Ratio and Indication
Are the benefits of short DAPT outweighing the risk?
Yes,
if the stent is safe enough
-> … how can we know?
-> … scientific evidence is essential.
if long DAPT is dangerous for the patient
-> … it certainly is for some?
-> HBR patients have an unmet clinical need!
General DES indication Specific HBR indication

6. BA9TM Drug 10 Times More Lipophilic than Sirolimus1
The BA9 Drug-Coated Stent for Ultra-Short DAPT
Selectively Micro-Structured Surface Holds Drug in Abluminal Surface Structures
Polymer-free Design
Rapid drug transfer into tissue
BMS-like in 1 month ?
Selectively Micro-Structured Surface Holds Drug in Abluminal Surface Structures
BA9TM Drug 10 Times More Lipophilic than Sirolimus1
Sirolimus
Zotarolimus
Everolimus
Biolimus A9TM 20 40 60 80
100 %
Highly lipophilic drug
Sirolimus analogue
Long tissue residence time
+/- 2.8% (valid for all drugs test)

7. Who Are the Patients at High Bleeding Risk ?
Systematically excluded from trials
Little clinical evidence
20% of cath lab volume
Today, they receive either
- BMS with high restenosis, or
- DES with shortened DAPT, with
little scientific evidence

8. Leaders Free Trial: Latest Evidence for Patients at High Bleeding Risk*
RRR -46% %
Def./Prob. Stent Thrombosis
∆ =
+0.1%
+0.1%
RRR -20%
* Urban P, Meredith IT, Abizaid A et al. Polymer-free Drug-Coated Coronary Stents in Patients at High Bleeding Risk. NEJM 2015 Nov 19; 373(21):

9. HBR Patients with ACS: 1 Month DAPT Only ?
RRR -59%
RRR -52%

10. Fundamentals of the New Leaders Free II Trial
Single-arm companion study to Leaders Free
Reference is BMS control arm of Leaders Free compared through propensity matching using the Leaders Free endpoints
Operational set up as similar as possible to Leaders Free, i.e. same inclusion criteria, same endpoints, same study procedures, same CEC, same CEC charter, same follow- up (+ 3y f/u)
Use the dataset of both trials as a backbone to apply for a specific label for HBR patients

11. Leaders Free II US Pivotal Trial – Design
BioFreedom™
DCS
Gazelle™
BMS R
2,466 Patients
HBR; 1 Mo DAPT
1:1
1,200 Patients
Card. Death, MI, ST
ci TLR
Second. Endpoints
Non-inferiority + Superiority comparison
(Propensity Score Method)
Leaders Free Trial
Leaders Free II Trial (US Pivotal)
Follow-Up:
1 Year
2 Years
3 Years

12. Leaders Free II Trial – Inclusion Criteria
Age ≥ 75 years
OAC planned after PCI
Baseline Hb < 11g / dl or transfusion during prior 4 weeks
Planned major surgery (within next year)
Cancer diagnosed or treated ≤ 3 years
Creatinine clearance < 40 ml / min
Hospital admission for bleeding during past year
Thrombocytopenia (< / mm3)
Any prior intra-cerebral bleed
Any stroke during the past year
Severe liver disease
NSAID or steroids planned after PCI
Anticipated poor DAPT compliance for other medical reason

13. Trial Organization Study Chairman: Marty Leon Principle Investigator:
Mitchell W. Krucoff; co-PI: Philip Urban
Study sites:
70 total; 47 USA, 7 Canada, 16 Europe
Statistics:
Stuart Pocock; T. Mc. Andrew (CRF)
DSMB:
B. Meier (Chair), J. Ambrose, H. Dauerman, M. Hong, S. Waxman
CEC:
R. Mehran (Chair), A. Baumbach, S. Cook, P. Kala,
J. Machecourt, F. Mauri, G. Olivecrona, S. Petronio,
F. Ribichini, L. Thuesen, A. Pichard (same CEC as in LF Trial)
CRO:
Syntactx, NY, Program Manger: Corie Diaz
CERC, Massy, France
e-CRF:
MERGE
Sponsor:
Biosensors Europe, Morges, Switzerland

14. Thank You !

15. Key Aspects of the Leaders Free Trial
Large, powered, randomized, double-blind landmark trial with clinical endpoints
Rigorously performed, sufficient for publication in the NEJM
Selection criteria for HBR patients likely valid for patients in the USA
Safety signal: Current US treatment practice of using BMS in HBR patients may do more harm than good.
Benefit of DCS most expressed in ACS
Minimal incremental increase in ST from 1 to 2y

16. Summary
The BioFreedom™ drug-coated stent (DCS) is available in more than 40 countries over the world, but not yet in the United States.
An European, large, double-blind, randomized trial – Leaders Free – has shown that the DCS is more efficacious and safer than BMS.
The trial outcomes point to a safety risk for HBR patients when they are treated with BMS, which is in part current practice in the US.
Treatment with the DCS and 1 month DAPT offers the potential for elevating the standard of care for patients at high bleeding risk (HBR).
To obtain FDA approval, an US single-arm companion trial to Leaders Free was designed to compare the US DCS results to the historic BMS control arm of Leaders Free.
Objective of the new US pivotal trial is to confirm the favorable Leaders Free results for the DCS in an American population of HBR patients.