1. 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

2. 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

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

4. 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

5. 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.

6. 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

7. 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.

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

9. An ‘On-the-Table’, Significant BP Reduction in All Patients (average BP decline: -28/-15mmHg)
Systolic BP
mmHG
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

10. 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

11. 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

12. 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
Months post Coupler Placement to Onset

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

14. 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 months
Safety Endpoint: Procedural and AEs through 12 months

15. 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

16. 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 months for antihypertensive crisis
24 hour ABPM ≥140 mmHg
Site expertise in HTN diagnosis and treatment

17. 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

18. 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

19. 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.)

20. 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

21. THE END