1. The Role of Research in Enhancing Clinical Practice
Noah Jones, MD, MPH
System Director, Structural Heart and Valve Center
May 10th, 2017

2. Introduction
~260 investigators conducting research across MCHS:  166 MDs  31 DOs  19 Nurses  14 Pharmacists  10 PhDs  2 DPMs  16 “Other “
121 research studies reviewed by the Mount Carmel Institutional Review Board (IRB) during current Fiscal Year 17

3. Introduction, cont’d
Private practice physician can reserve time to conduct clinical research
Physician investigator must take the initiative to seek out clinical research opportunities

4. Areas of Research Interest
Transcatheter Aortic Valve Replacement (TAVR)
Mimimally invasive treatment for aortic stenosis
Approved in U.S. late 2011
Pulmonary Embolism (PE)
Embolism of the pulmonary artery or one of its branches, usually caused by an embolus from a blood clot in a lower extremity
Hemodynamically unstable or “massive” PE
Hemodynamically stable or “submassive" PE if there is associated right ventricular strain

5. Structural Heart Clinical Trials PARTNER 3 – Low Risk
2016 – present
Sponsor: Edwards Lifesciences
Status: currently enrolling
Prospective, Randomized, Controlled, Multi-center Study to Establish the Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low risk Patients who have Severe, Calcific, Aortic Stenosis Requiring Aortic Valve Replacement
Purpose: establish safety and effectiveness of Edwards SAPIEN 3 (Edwards Lifesciences, Irvine, CA) Transcatheter Heart Valve (THV) in patients with severe, calcific aortic stenosis who are at low operative risk for standard aortic valve replacement (AVR)

6. Structural Heart Clinical Trials PARTNER 3, cont’d
Prospective, randomized, controlled, multi-center trial
Patients randomized 1:1 to receive TAVR with Edwards SAPIEN 3 or aortic valve replacement with commercially available surgical bioprosthetic valve - Subset of patients from each study arm to be enrolled in computed tomography sub-study at select sites
1,228 patients enrolled - CT sub-study: 200 patients from each study arm - Alternative access registry: additional 100 patients
Patients followed for 10 years
Primary endpoint: composite of all-cause mortality, all stroke, and rehospitalization (valve- or procedure-related, including heart failure) at 1 year post procedure

7. Structural Heart Clinical Trials EARLY TAVR
2017
Sponsor: Edwards Lifesciences
Status: site initiation
Evaluation of Transcatheter Aortic Valve Replacement Compared to SurveilLance for Patients with AsYmptomatic Severe Aortic Stenosis: EARLY TAVR trial
Objective: to establish safety and effectiveness of Edwards SAPIEN 3 (Edwards Lifesciences, Irvine, CA) Transcatheter Heart Valve (THV) compared with clinical surveillance (CS) in asymptomatic patients with severe, calcific aortic stenosis

8. Structural Heart Clinical Trials Early TAVR, cont’d
Prospective, randomized, controlled, multi-center trial.
Patients randomized 1:1 to receive either transcatheter aortic valve replacement (TAVR) with the Edwards SAPIEN 3 THV or clinical surveillance
1,109 patients to be enrolled and up to 1,000 patients followed in registry
Patients to be followed for 5 years
Primary endpoint: superiority comparison using log-rank test comparing survival curves through 2 years

9. Peripheral Vascular Clinical Trials OPTALYSE PE
2015 – present
Sponsor: EKOS Corp (now BTG)
Status: closed to enrollment; in follow-up
Randomized, parallel, multi-arm, multi-center study of the OPTimum Duration of Acoustic Pulse ThromboLYSis ProcEdure in the Treatment of Acute Submassive Pulmonary Embolism
EkoSonic® Endovascular System (EKOS) employs high frequency (2-3MHz), low power ultrasound to facilitate delivery of thrombolytic agents to intravascular treatment site in pulmonary arteries
Acoustic Pulse Thrombolysis (APT) Procedure: clinical use of EKOS in combination with r-tPA administration

10. Peripheral Vascular Clinical Trials OPTALYSE PE, cont’d
Objective: determine the optimum dose of thrombolytic and duration of the ultrasound procedure (together are defined as the APT Procedure) as a treatment for acute submassive PE
Primary efficacy endpoint: change in the ratio of measurement of Right Ventricular to Left Ventricular diameter ratio (RV/LV) as measured by CTA from baseline to 48 hours after start of APT procedure
Primary safety endpoint: major bleeding within 72 hours after initiating APT procedure

11. Peripheral Vascular Clinical Trials OPTALYSE PE, cont’d
Results: Eighty-three subjects at 17 centers treated with Ultrasound-assisted Catheter-Directed Thrombolysis (USCDT) bilaterally per randomized dose/duration - All 4 treatment groups showed significant reductions in primary efficacy endpoint of reduction in RV/LV 48 hours after starting treatment
Lower dose and duration USCDT minimizes risk of major bleeding while improving measures of RV function - Important implications for shortening procedure time, minimizing tPA exposure, and increasing cost effectiveness
Accepted as oral presentation at Cardiovascular and Interventional Radiological Society of Europe (CIRSE), September 2017, Copenhagen, Denmark (Sterling KM, Jones N, Piazza G, Goldhaber S, and Tapson V)

12. Peripheral Vascular Clinical Registries Registry of Angiovac Procedures In Detail
2015 – present
Sponsor: David Geffen School of Medicine at UCLA
Status: enrolling
Purpose: to collect information on the Angiovac procedure and Angiovac device used in removal of fresh, soft thrombi or emboli during extracorporeal bypass in a registry (outcomes database)
Primary objective: to determine procedure-related mortality associated with use of Angiovac device
Primary endpoint: all-cause mortality within 24-hours of deployment of device will be complemented by secondary endpoints related to patient demographics, procedural specifics, and early clinical outcomes

13. Peripheral Vascular Clinical Trials SEATTLE II
Sponsor: EKOS Corp
Status: Completed
Submassive and Massive Pulmonary Embolism Treatment with
Ultrasound AcceleraTed Thrombolysis ThErapy (SEATTLE II)
Prospective, single-arm, multi-center trial of EkoSonic® Endovascular System and Activase for acute pulmonary embolism
EKOS EkoSonic® Endovascular Device employs high frequency (2-3MHz), low power ultrasound to facilitate delivery of therapeutic agents to intravascular treatment site in peripheral vasculature

14. Peripheral Vascular Clinical Trials SEATTLE II, cont’d
Purpose: to obtain performance and safety data for EKOS EkoSonic® Endovascular Device when used in conjunction with recombinant t-PA as treatment for acute pulmonary embolism (PE)
Patients with acute symptomatic massive or submassive PE confirmed by contrast-enhanced chest CT with embolus located in at least one main or proximal lobar pulmonary artery and end-diastolic diameter RV/LV ratio > 0.9 on CT
Patients ≥ 18 years of age and index PE symptoms for ≤14 days

15. Peripheral Vascular Clinical Trials SEATTLE II, cont’d
Up to 120 subjects in up to 40 centers within U.S.
Efficacy: determine whether treatment with USCDT will decrease the ratio of RV to LV diameter within 48 ± 6 hours in patients with massive or submassive PE
Safety: determine frequency of major bleeding within 72 hours of initiation of USCDT procedure in patients with massive or submassive PE

16. Peripheral Vascular Clinical Trials SEATTLE II, cont’d

17. Peripheral Vascular Clinical Trials SEATTLE II, cont’d

18. Carotid Interventions Clinical Trials SAPPHIRE
2011 – 2014
Sponsor: Cordis
Status: closed
Carotid Stenting and Angioplasty With Protection in Patients At HIgh-Risk for Endarterectomy (SAPPHIRE Worldwide Registry)
Prospective trial with 21,008 patients enrolled - Mean age 72 years; 61% men - Treated with CAS using nitinol carotid stent (Precise, Cordis) and distal embolic protection with an emboli capture guidewire (Angioguard XP/RX, Cordis) between
Patients considered high-risk for carotid endarterectomy and 30% had symptomatic carotid artery disease - Patients eligible if 80% stenosis if asymptomatic and 50% stenosis if symptomatic
November 3, 2015 LAS VEGAS D. Christopher Metzger, MD, FACC, FSCAI, presented at VIVA 15.

19. Carotid Interventions Clinical Trials SAPPHIRE, cont’d
Results: at 30 days, rate of major adverse events = 4.4% % of patients had a stroke, 1.2% died, and 0.5% had MI
Major adverse events more likely to occur in patients: - Aged 75 years vs. younger patients (5.9% vs. 3.2%; P < ) - Those at high physiologic risk vs. high anatomic risk (5.1% vs. 3%; P < ) - Those who were symptomatic vs. asymptomatic (5.7% vs. 3.8%; P < )
Largest predictor of stroke after CAS was age 75 years (OR = 2.05; 95% CI, ) - Other predictors: symptoms, need for concomitant carotid revascularization with bypass surgery, and renal insufficiency

20. Advantages of Conducting Clinical Trials
Provide latest innovative treatments to our patients
Investigators obtain experience in use of drug/device before others (professional / skill advancement)
Patients may be more likely to choose healthcare system that offers research
Community recognition that MCHS does do research

21. Advantages of Conducting Clinical Trials, cont’d
Satisfaction of answering important questions which will improve health of our patients
Provide opportunity for scholarly activity in the community hospital setting
Ability to do research may attract high-caliber physicians / residents

22. Evolution of CV Trials at MCHS
1st 3 months
Currently 8 CV clinical trials/registries open
Angioplasty, stents
US-assisted thrombolysis
Anti-inflammatory medication
Percutaneous
thrombectomy
TAVR
Electrophysiology

23. Steps Needed to Open a Clinical Trial Stage 1: Evaluate Trial
Execute CDA: Confidentiality Disclosure Agreement
Receive sponsor protocol
Initial contact w/ sponsor
End
PI & MCHS Review Protocol:
Feasibility
Interest
Clarifications No
Sponsor Site Qualification Visit: general operations conducive to trial?
Continue?
Yes
Next page

24. Steps Needed to Open a Clinical Trial Stage 2: Trial Preparation
Trial budget review
Attend sponsor’s investigator meeting
IRB Review: protocol, informed consent, etc
Negotiate clinical trial agreement
Trial documents:
CV, med license,
ethics training
etc.
Approvals
Medicare coverage analysis
Next page

25. Steps Needed to Open a Clinical Trial Stage 3: Trial Conduct
Study Set-up
Lab sample processing, shipping
Begin enrolling!
PI, coordinator trial-specific training
Site Initiation Visit with Sponsor
Drug/Device storage, billing

26. Current Cardiac & Vascular Studies
Edwards Lifesciences PARTNER 3: a Prospective, Randomized, Controlled, Multi-Center Study to Establish the Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low Risk Patients who have Severe, Calcific, Aortic Stenosis Requiring Aortic Valve Replacement, PI -Noah Jones, MD
Cardiovascular Inflammation Reduction Trial (CIRT), PI - Douglas VanFossen, MD

27. Current Cardiac & Vascular Studies
Edwards Lifesciences EARLY TAVR: Evaluation of Transcatheter Aortic Valve Replacement Compared to SurveiLance for Patients with AsYmptomatic Severe Aortic Stenosis, PI - Noah Jones, MD
Medtronic AdaptResponse: Prospective, Randomized, Controlled, Interventional, Single-Blinded, Multi-Center, Post-Market, Global Resynchronization Therapy in Heart Failure Clinical Study, PI -Joshua Silverstein, MD

28. Current Cardiac & Vascular Studies
EKOS-12 OPTALYSE PE : Study of the OPTimum Duration of Acoustic Pulse ThromboLYSis ProcEdure in the Treatment of Acute Submassive Pulmonary Embolism study, PI - Noah Jones, MD
Medtronic World-wide Randomized Antibiotic EnveloPe Infection PrevenTion Trial (WRAP-IT): a Randomized, Prospective, Multi-center, Single Blinded, Post-market, Interventional Clinical Study, PI -Kamel Addo, MD

29. Current Cardiac & Vascular Studies
Boston Scientific APPRAISE ATP: Assessment of Primary Prevention patients Receiving An ICD - Systematic Evaluation of ATP, PI - Kamel Addo, MD
RAPID Registry: Registry of Angiovac Procedures in Detail, PI- Noah Jones, MD

30. Investigator-Initiated Research
TAVR: Do Cardiac Troponins or BNP Levels Predict Outcomes in TAVR Patients? Noah Jones, MD
PE: Acute Procedural Results and In-Hospital Outcomes for Submassive PE Treated with Low Dose Ultrasound-Facilitated Catheter-Directed Thrombolysis: Retrospective Analysis from a Single Health System, Noah Jones, MD

31. Acknowledgements Colin Edwards- Regional Director research
Charles Sanders – Vice President Medical Education and Research
Lynn Shaffer - Biostatistician
Kristi Phillips-Burkhardt – Lead Structural Heart Coordinator
Lora Mahoney – Structural Heart Nurse Navigator

32. “Imagination is more Important than Knowledge..”
Thank you and good luck
“Imagination is more Important than Knowledge..”
Albert Einstein