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The BLAST Trial B iorest L iposomal A lendronate with S tenting s T udy

The BLAST Trial B iorest L iposomal A lendronate with S tenting s T udy. Targeted Anti-Inflammatory Systemic Therapy for Restenosis. Shmuel Banai, MD Tel Aviv medical Center Tel Aviv, ISRAEL. Disclosure Statement of Financial Interest.

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The BLAST Trial B iorest L iposomal A lendronate with S tenting s T udy

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  1. The BLAST TrialBiorest Liposomal Alendronate with Stenting sTudy Targeted Anti-Inflammatory Systemic Therapy for Restenosis Shmuel Banai, MD Tel Aviv medical Center Tel Aviv, ISRAEL

  2. Disclosure Statement of Financial Interest I, Shmuel Banai, DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.

  3. Background Inflammation is the hallmark of Atherosclerosis and Restenosis Monocytes/macrophages are the key mediators of inflammation systemically and locally within the vessel wall Patients in a pro-inflammatory state are at higher risk for Restenosis

  4. BIOrest LABR-312 Cell # [% of baseline] Monocyte Modulation 0 1 5 10 50 100 Concentration [uM] Days after Infusion • A highly selective systemic monocyte inhibitor • Produces a transient effect lasting several days EC Macrophages 0 2 4 6 Danenberg et al, Circulation 2002 Danenberg et al, Circulation 2003 Danenberg et al, JCP 2003

  5. BLAST – BIOrest Liposomal Alendronate with Stenting sTudy BIOrest LABR-312 is a unique, specific and transient means of modulating monocytes HYPOTHESIS: Modulation of systemic and local inflammation will attenuate intimal hyperplasia after BMS implantation OBJECTIVE: To assess the safety and efficacy of a single IV bolus of LABR-312 in the treatment of de novo stenotic lesions in native coronary arteries in a population undergoing PCI with implantation of a BMS

  6. BLAST Trial Phase II dose-finding, randomized, multi-center, prospective, double blind. N=225 Patients Study PI: Prof. Shmuel Banai – Tel Aviv Medical Center Participating Medical Centers and PI’s: • Tel Aviv Sourasky – S. Banai • ShaareZedek – Y. Almagor • Baruch Padeh – Y. Hasin • Bnei Zion – U. Rosenschein • Rabin – R. Kornowski • Sheba – V. Guetta • Lady Davis – B. Lewis • Meir – M. Mosseri • Kaplan – O. Ayzenberg • Hillel Yaffe – A. Frimerman • Western Galilee – S. Atar

  7. BLAST Trial – Parties Involved

  8. BLAST Trial - Study Endpoints Primary Endpoint: In-Stent angiographic Late Loss @ 6m Secondary endpoints: IVUS measurements, clinical outcomes, monocyte count and function by FACS (Fluorescence Activated Cell Sorter) Pre-Specified subgroup analyses including: Diabetes Baseline monocyte count Unstable Angina

  9. Total Patients Recruited N=225 Randomization 1:1:1 Placebo (saline) N=74 High Dose (10µg LABR-312) N=74 Low Dose (1µg LABR-312) N=77 BMS Stenting+Drug Administration QCA, IVUS, Blood sampling for monocytes @ Screening, 0, 8, 16, 24 h 30d Clinical f/u 6m Clinical+Angiographic f/u Per-Protocol Analysis 1º Endpt Placebo N=57 High Dose N=59 Low Dose N=56 6m IVUS f/u subset Placebo N=26 High Dose N=26 Low Dose N=31

  10. Main Inclusion/Exclusion Criteria De-novo lesions in native coronary arteries LL<30mm, 2.5mm<RVD<3.5mm, 1 or 2 VD No bifurcations, LM, Ostial Up to 3XULN cTn  DM  NSTEMI  Unstable Angina Pro-Inflammatory Patients

  11. Clinical and demographic characteristics

  12. BLAST Trial Main Safety Results CEC Adjudicated @ 180d * MI excluding peri-procedural = 1.8%, 1.8%, 1.7% Placebo, Low Dose, High Dose respectively

  13. BLAST Trial Main Efficacy Results

  14. But are they truly the same? Non-Gaussian p<0.005 Gaussian p>0.25

  15. Cumulative Distributions

  16. Hypothesized Differential Response

  17. Protocol mandated sub-group analysis Based on inflammatory state • Diabetes • Baseline monocyte count

  18. Diabetic Subgroup

  19. Pre-Specified Inflammatory Subgroup 50-50 Split based on baseline monocyte count * Low Monocytes = Less than median value pre-injection * High Monocytes = More than median value pre-injection

  20. Conclusions In the overall study cohort, LABR-312 had no average effect on in-stent Late Loss In the pro-inflammatory patients (mandated subgroup analysis including >50% of the cohort), there was a pronounced, statistically significant reduction in Late Loss with LABR-312 This differential response could be identified and predicted a-priori provides the potential for personalized medicine Future clinical trials will likely focus on the dichotomization and extension of treatment effect

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