US ROX HTN Clinical Trial Design: Reason and Rational Krishna Rocha-Singh, MD Chief Scientific Officer Prairie Heart Institute Saint John’s Hospital Springfield, IL

Krishna Rocha-Singh, MD 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 Grant/Research Support Consulting Fees/Honoraria Major Stock Shareholder/Equity Royalty Income Ownership/Founder Intellectual Property Rights Other Financial Benefit Medtronic Medtronic, Alucent, Zimmer-BioMet, ROX Medical PQ Bypass None Convergence Consulting, LLC Yes VIVA Board Member

The Pathophysiology of Structural Hypertension Feed-forward loop involving blood pressure parameters, circulatory damage and arterial stiffness Kapil et al. Curr Hypertens Rep 2015

Age Related loss of Aortic Elasticity Underlies HTN Treatment Failure 85% of uncontrolled patients are over 50 yr % Uncontrolled Isolated Systolic Htn ISH aka, ‘Structural Hypertension’ Sys/Dias Htn As we look at which patients are struggling most with control of their hypertension, it is the older patients, over age 50yrs who comprise 85% of the uncontrolled hypertension patients. They are as adherent to medications, but are getting less relief or effect. This is because their hypertension has fundamentally changed to predominantly Isolated Systolic Hypertension or Structural Hypertension do to arterial and aortic stiffening. Isolated Diastolic Htn Franklin et al, Hypertension 2001

Arteriovenous ROX Coupler and deployment catheter ROX Coupler Device Arteriovenous ROX Coupler and deployment catheter Reproduced by permission of ROX Medical, San Clemente, CA, USA.

ROX Coupler Using a venous segment to reduce effective arterial volume : Restores aortic elasticity at lower filling volumes in aged vessels Reduces mean and peak BP Reduces BP variability and volume sensitivity Reducing pulse wave propagation velocity eliminates systolic pressure stacking The solution is to use a venous segment to reduce effective arterial volume by siphoning off a fixed amount of blood, thus allowing the aorta ot operate at a more optimal position on its stretch strain relationship

Increase Arterial Compliance, Decrease Vascular Resistance Fixed 4mm Diameter Arteriovenous Anastomosis ~ 800 cc shunt Increase Arterial Compliance, Decrease Vascular Resistance Immediate, Verifiable Response No Sham, Placebo, Hawthorne Effect Placement between Iliac Artery & Vein CLOSED 182 mmHg CLOSED 180 mmHg OPEN 158 mmHg The coupler attaches the iliac artery and vein, with a 4 mm diameter anastomosis- allowing only 800 cc of blood to shunt rightward. The device causes an IMMEDIATE reduction in bp in ALL PATIENTS, and it can be refersed immediately by blocking the shunt There is no sham effect, o placebo effect no hawthorne effect- this is a biophysical certainty to reduce bp The ROX Coupler is NOT commercially available in the United States. CAUTION: Investigational device. Limited by Federal (or United States) law to investigational use. The ROX Coupler is CE marked for Hypertension and is commercially available in the European Union.

Immediate, Significant BP Reduction Upon Placement of the ROX Coupler The immediate BP reduction eliminates the possibility of placebo, sham or Hawthorne effect

An ‘On-the-Table’, Significant BP Reduction in All Patients (average BP decline: -28/-15mmHg) Systolic BP 186-180 mmHG 150-153 mmHG The bp fall is immediate, significant and sustained. To date, no patient has lost their bp effect unless they have chosen to stop their baseline medications With a 800cc shunt, well below the shunt size associated with high output failure which is on the order of 6-8 l.min not 800 cc.min, there has never been a spontaneous closure of this anatstomosis. ~72 ~60 ( mmHg ) Diastolic BP

ROX CONTROL HTN Study: Six-Month Results Change from baseline in blood pressure at 6 months Data are mean (SD). SBP=systolic blood pressure. DBP=diastolic blood pressure. OBP=office blood pressure. ABP=ambulatory blood pressure. AV=arteriovenous. Lobo et al. Lancet 2015

ROX CONTROL HTN Study: Six-Month Results Includes left and right side implants Only right side US trial Adverse events related to AV coupler placement or device Lobo et al. Lancet 2015

Venous Stenosis: An Easily Managed Complication Venous stenosis, a fibrotic “hour-glass” narrowing of the vein occurs cranial to the anastomosis Late onset edema is the typical sign, 6-9 months post procedure PTA with venous stenting resolved stenoses ~100% success rate with no reoccurrences Venous Stenosis Occurrence - RH-02 HTN Randomized Trial n=42 There is one almost cosmetic AE associated with the procedure. In a third of patients, proximal venous stenosis presentst with unilateral leg edema by the 9th month. It is permanently treated with a venous stent. The complications of this venous stenosis pale by comparison to the clinical complications of being assigned to the control group. And unlike drug AE like diabetes, gout, renal failure, gynecomastic and enectrolyte disturbances, this AE is reversible. 100% Resolution Patients with VS 0 3 6 9 12 15 18 Months post Coupler Placement to Onset

Approved FDA IDE to initiate a pivotal RCT for HTN control Trial enrollment expected to begin early Q2 2017

The US ROX HTN Trial Design: Impact on AV Fistula Physiology on Trial Design? 1:1 randomized sham controlled, double-blinded (patient and HTN physician) trial Primary Endpoint: Change in mean 24 h ABPM at 6 months --Secondary Endpoint: Change in mean OBP at 6 months Safety Endpoint: Procedural and AEs through 12 months

BP Medications Run-In Screening A Sustainable Dosing Regimen Stable regimen of at least 3 months consisting of a diuretic AND --Two additional anti-hypertensives of difference classes; guideline- or label- directed dosing; OR --Documented intolerance to at least three of 4 major classes of anti-hypertensives (ACE, ARB, B-blocker, CCB) Maintain drug regimen for at least 6 months post-randomization

The US ROX HTN Trial Design: Key Inclusion Criteria Key Inclusion Criteria: --OBP ≥155 mmHg at all screening visits AND ≥160 at one visit; OR OBP ≥150 mmHg AND one ER visit or hospitalization in the past 12 months for antihypertensive crisis 24 hour ABPM ≥140 mmHg Site expertise in HTN diagnosis and treatment

The US ROX HTN Trial Design: Key Exclusion Criteria eGRF <45 mL/min/1.73m2 Significant venous disease and/or PAD Moderate/severe valvular disease LVEF ≤45%, mean PAP >25mmHg, PCWP >15 mmHg at time of right heart cath History of DVT/PE

Minimizing the Hawthorne Effect Patients will attend 3 screening visits: --Measure OBP at each screening visit --Home medication compliance logs to reinforce consistence, stable dosing ECG, TTE, venous DUS and ABIs will also be performed

Post-Randomization Follow-up 1, 3, 6, 12 month clinical follow-up performed by a blinded investigator/designee Goal to maintain pre-randomization medical regimen through 6-months Safety considerations will allow for medication adjustments (hypotension/hypertension, etc.)

US ROX HTN Trial The first therapy which is effective for HTN consequent to loss of aortic elasticity- “Adult Hypertension” The ROX randomized, double-blinded, sham controlled trial in hypertensive patients on a ‘stable and consistent’ antihypertensive regimen, maintained through 6-months will assess the safety and efficacy of this novel concept

THE END