What Happened in the IN.PACT Deep Trial. Zaheed Tai, DO,FACC,FSCAI Bos4ck Heart Center Winter Haven, FL

Transcription

1 What Happened in the IN.PACT Deep Trial Zaheed Tai, DO,FACC,FSCAI Bos4ck Heart Center Winter Haven, FL

2 BTK Revasculariza>on Challenges Long, complex, ocen calcified nature of lesions 1 OCen associated with mul4level disease, thus success inflow- and ouklow- dependent 2 Small caliber vessels High restenosis rate 3 Limb salvage poorly correlated to primary patency 3 Literature landscape dominated by small series and case studies 1 Liistro, et al. Circ: 128: (2013). 2 Norgren, et al. JVS: 45: Suppl S: S5-67 (2007). 3 Kudo, et al. JVS: 41: (2005).

3 Small Scale Success DEBATE- BTK (Liistro, et al.) 1 Single- center, randomized (1:1) N = 132, 100% diabe4cs 12.9cm mean lesion length (DCB arm), 77.5% CTO IN.PACT Amphirion (Medtronic) v POBA 12- mo Results: 18% TLR 27% binary restenosis (PSVR > 2.5) 17% re- occlusion 1 Liistro, et al. Circ: 128: (2013).

4 Small Scale Success DEBATE- BTK (Liistro, et al.) 1 Leipzig Registry 2 Single center N = 104 (73% Diabe4cs) 17cm mean lesion length, 62% CTO 12- mo results: 17.3% TLR 3- mo results: 27.4% binary restenosis 8.3% re- occlusion These studies highlight potenhal of DCB for BTK revascularizahon 1 Liistro, et al. Circ: 128: (2013). 2 Schmidt, et al. JACC: 58: 11: (2011).

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6 Zeller, et al. JACC 64: (2014).

7 Objec>ves and Endpoints Objec>ve: Evaluate the safety and efficacy of IN.PACT Amphirion DEB vs. standard PTA for infrapopliteal revasculariza4on in pa4ents with CLI Primary Efficacy Endpoints: 1. Angio- cohort: Late Lumen Loss at 12- month or at the 4me of TLR 2. All pa3ents: clinically driven TLR at 12 months due to RC or wound deteriora4on as adjudicated by the Wound Corelab [1] Primary Safety Endpoint: 6- month all cause death, major amputa4on, clinically driven TLR Key Secondary Endpoints: Amputa4on- Free Survival, Major Adverse Events, All- Cause Mortality, Major and Minor Amputa4ons, Wound Healing, Device, Technical and Procedural Success 1. increased size of pre-existing wound or occurrence of a new wound(s)

8 Eligibility Criteria General (Key) Inclusions Rutherford Class Age years + life expectancy >1 year Target vessel: infrapopliteal (incl. Tibio Peroneal Trunk) above the ankle [1] RVD 2-4 mm Single or mul4ple lesions ( 70%) of any length At least one non occluded crural vessel with documented run- off to the foot either direct or through collaterals Angio Cohort (Key) Inclusions Single or mul4ple adjacent lesions ( 70%) with cumula4ve length of 100 mm that can be covered by a single IN.PACT Amphirion General (Key) Exclusions Planned major index limb amputa4on Inflow impaired or non re- established Failure to cross the target lesion with a guide wire ISR Thrombus or aneurysm Angio Cohort (Key) Exclusion GFR <30 ml/min except for pa4ents with ESRD on chronic haemodialysis 1. non-target lesions in pedal arteries can be treated at operator discretion, but only with conventional PTA

9 Trial Design Enrollment = 358 subjects Informed Consent Randomized 2:1 DEB: PTA Clinical cohort: All subjects Angio cohort (subset) Single lesion < 10 cm GFR > 30 ml/min [1] Angio eligible = 168 DEB = 113 PTA = 54 Screening & Angiography Total enrollment = 358 DEB = 239, PTA = 119 Angio excluded = 191 DEB = 126 PTA = Except pa3ents with ESRD, on chronic haemodialysis and with life expectancy >1 year Angiographic outcomes Clinical outcomes

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17 Conclusion IN.PACT Deep failed to meet any 1 efficacy endpoint Raised concerns because of the higher amputa4on rate

18 What went wrong? Why were the results not the same as earlier preliminary studies?

19 Amphiron DEB Rocha- Singh:The IN.PACT DEEP trial: PuMng the results into context

20 Amphirion IN.PACT DEB in BTK Study Design and Key Eligibility Criteria DEBATE- BTK* IN.PACT DEEP Inves>gator ini>ated Single center Prospec>ve randomized (1:1) DEB vs. PTA Self adjudicated No external monitoring *Liistro et al, Circula4on 2013 Industry sponsored Prospec>ve, Mul>center, Randomized (2:1) DEB vs PTA Ind. Data Safety Monitoring Ind. Clinical Event Commibee Ind. Angiographic Corelab Ind. Wound Corelab Wound Measurement through Electronic Reader External Monitoring 100% Source Data Verifica3on

21 Issues with IN.PACT Deep Trial Single center vs mul4center results

22 Amphirion IN.PACT DEB in BTK Study Design and Key Eligibility Criteria RC Diabetes DEBATE- BTK Stenosis / occlusions >40 mm in at least 1 >bial vessel with distal run- off GFR<30ml/min and ESRD and dialysis included RC Age18-85 Stenosis / occlusions of any length in at least one >bial vessel with distal run- off RVD 2-4mm IN.PACT Deep Lesion length 100mm (angio cohort) GFR<30ml/min (except ESRD and dialysis). (exclusion criteria in angio cohort Foot arteries can be dilated only with conven>onal balloon even in DEB cohort Lesions do not reflect those observed in daily prac4ce in angio cohort

23 Issues with IN.PACT Deep Trial Single center vs mul4center results Pa4ent popula4on may not have been representa4ve of everyday pa4ents

24 Amphirion IN.PACT DEB in BTK Endpoints DEBATE- BTK Primary Endpoint: 12- month binary (>50%) Restenosis Rate Secondary Endpoints: 12- month TLR; 12- month Occlusion rate. Index limb major amputa>on Sample size: Hypothesis:50% RRR in restenosis in DEB group. Minimum of 63 evaluable lesions per group 90% power (2- sided 5% significance level) The number of lesions per group was further increased to 75 to maximize study power. Restenosis for PTA was expected to be 50% IN.PACT Deep Primary Efficacy Endpoints: Angio- cohort: Late Lumen Loss at 12 months All pa3ents: clinically driven TLR at 12 months Primary Safety Endpoint: 6- month all cause death, major amputa4on, clinically driven TLR Key Secondary Endpoints: Amputa4on- Free Survival, Major Adverse Events, All- Cause Mortality, Major and Minor Amputa4ons, Wound Healing, Device, Technical and Procedural Success. Sample size: Angio cohort 3 primary EP COMPLEX MULTIPLE ISSUES NOT EXCLUSIVELY DEPENDING ON DEB EFFICACY

25 Issues with IN.PACT Deep Trial Single center vs mul4center results Pa4ent popula4on may not have been representa4ve of everyday pa4ents Complex Endpoints not necessarily dependent on DEB efficacy Small sample size and 2:1 randomiza4on increased the risk of random error

26 IN.PACT Deep Baseline pa>ents characteris>cs Previous Target Lesion Revasculariza>on

27 IN.PACT Deep Baseline pa>ents characteris>cs Inflow lesions

28 Issues with IN.PACT Deep Trial Single center vs mul4center results Pa4ent popula4on may not have been representa4ve of everyday pa4ents Complex Endpoints not necessarily dependent on DEB efficacy Small sample size and 2:1 randomiza4on increased the risk of random error Inflow disease may pose a higher risk for BTK index TLR

29 Angio f/u: 61/113=54% DEB 31/54=57% PTA

30 Issues with IN.PACT Deep Trial Single center vs mul4center results Pa4ent popula4on may not have been representa4ve of everyday pa4ents Complex Endpoints not necessarily dependent on DEB efficacy Small sample size and 2:1 randomiza4on increased the risk of random error Inflow disease may pose a higher risk for BTK index TLR Approximately 50% loss of pa4ents to angiographic follow- up

31 IN.PACT DEEP: 12- mo Results IN.PACT Amphirion performed comparably or favorably to historical PTA 12- month Amputa4on Rate Historical PTA performance: 10-14% IN.PACT DEEP PTA performance: 3.6% IN.PACT DEEP DCB performance: 8.8% [7] [7] Zeller presented at LINC January Lejay, et al. Acta Chir Belg 109: (2009). 2. Romi4, et al. JVS 47: (2008). 3. Adam, et al. Lancet 366: (2005). 4. Rocha- Singh, et al. CCI 80: (2012). 5. Scheinert, et al. JACC 60: (2012). 6. Iida, et al. Eur J Vasc Endovasc Surg 43: (2012). 7. Zeller, et al. JACC 64: (2014).

32 Issues with IN.PACT Deep Trial Single center vs mul4center results Pa4ent popula4on may not have been representa4ve of everyday pa4ents Complex Endpoints not necessarily dependent on DEB efficacy Small sample size and 2:1 randomiza4on increased the risk of random error Inflow disease may pose a higher risk for BTK index TLR Approximately 50% loss of pa4ents to angiographic follow- up PTA results are not consistent with historical results

33 Safety Endpoints 6- month Death, Major Amputa>on or CD TLR 12- month Major Amputa4on 12- month All- Cause Mortality 17.7% (41/232) 15.8% (18/114) (non- inferiority) (superiority) 8.8% (20/227) 3.6% (4/111) % (23/227) 8.1% (9/111) month Wound- Healing 73.8% (121/164) 76.9% (70/91) month CD TLR 9.2 % (18/196) 13.1% (14/107) TLR rate in amputated pa4ents?????? A possibility to explain this high amputa4on rate is that pa4ents did not follow a dedicated pathway for healing surveillance and were probably not referred to the interven4onalist in due 4me

34 Issues with IN.PACT Deep Trial Single center vs mul4center results Pa4ent popula4on may not have been representa4ve of everyday pa4ents Complex Endpoints not necessarily dependent on DEB efficacy Small sample size and 2:1 randomiza4on increased the risk of random error Inflow disease may pose a higher risk for BTK index TLR Approximately 50% loss of pa4ents to angiographic follow- up PTA results are not consistent with historical results No standardized wound care across sites for equaliza4on of treatment

35 LLL- Product? No treatment effect Lack of drug effect? Recalled IN.PACT Amphirion Current IN.PACT Admiral Coating Method Balloon Material Manually-coated on folded balloon High surface energy Automatically-coated on inflated balloon Low surface energy Non- uniform coa4ng Lower drug transfer Uniform coa4ng Higher drug transfer

36 Issues with IN.PACT Deep Trial Single center vs mul4center results Pa4ent popula4on may not have been representa4ve of everyday pa4ents Complex Endpoints not necessarily dependent on DEB efficacy Small sample size and 2:1 randomiza4on increased the risk of random error Inflow disease may pose a higher risk for BTK index TLR Approximately 50% loss of pa4ents to angiographic follow- up PTA results are not consistent with historical results No standardized wound care across sites for equaliza4on of treatment Insufficient drug delivery

37 Summary Small scale series have shown promise for DCB in BTK revasculariza4on IN.PACT Deep observa4ons Sta4s4cal baseline variances in two cohorts may confound interpreta4on Lack of DCB efficacy possibly due to insufficient drug delivery by older genera4on device High risk subjects predisposed to safety event independent of interven4on DCB major amputa4on rate consistent with historical data and there were no unusual events caused by IN.PACT Amphirion Unprecedented, favorable PTA major amputa4on rate Sample size and excessive loss of follow- up in IN.PACT Deep warrant further study of DCB in CLI popula>on

38 What Happened in the IN.PACT Deep Trial Zaheed Tai, DO,FACC,FSCAI Bos4ck Heart Center Winter Haven, FL