REDUCED 1 - Renal Denervation Using Ultrasonic Catheter EmitteD Energy Study /

Clinical Evaluation of the Therapeutic Intra-Vascular Ultrasound (TIVUS™) System for Renal Denervation in Patients With Uncontrolled Stage 2 Hypertension

This is a prospective, multicenter, non-randomized, open-label clinical study of the safety and performance of the TIVUS™ System in subjects with uncontrolled stage 2 hypertension in order to assess the safety and effectiveness of the TIVUS™ System when used for renal artery denervation. The study will assess the acute and chronic safety of the procedure as well as the reduction in 24-hour ambulatory mean systolic blood pressure from baseline to 3 months after the procedure.

Nearly half of adults in the United States (108 million, or 45%) have hypertension defined as a systolic blood pressure ≥ 130 mm Hg or a diastolic blood pressure ≥ 80 mm Hg or are taking medication for hypertension. Hypertension is associated with cardiovascular and renal pathologies and leads to death if not treated appropriately. The cardiovascular risk factor doubles with each 20/10 mm Hg elevation in BP values above 115/75 mm Hg.

The current first-line therapy for hypertension involves change in life-style (i.e., diet and exercise) and various medications. However, only about 1 in 4 treated adults (24%) with hypertension have their condition under control. Thus, they are at increased risk for the major side effects of chronically elevated blood pressure, myocardial infarction, stroke, renal disease and heart failure. High blood pressure was a primary or contributing cause of death for more than 494,873 people in the United States in 2018, and was estimated to affect around 1.13 billion people worldwide and resulted in approximately 10 million deaths worldwide, in 2015.

About half of adults (45%) with uncontrolled hypertension have a blood pressure of 140/90 mm Hg or higher, now defined as Stage 2 hypertension. This includes 37 million U.S. adults. About 30 million adults are recommended to take medication. Almost two out of three of this group (19 million) have a blood pressure of 140/90 mm Hg or higher. The other 17 million adults are taking medications but are unable to lower their blood pressure below 140/90 mm Hg and are thus at increased risk for the risks associated with uncontrolled high blood pressure9. High blood pressure costs the United States about $131 billion each year, averaged over 12 years from 2003 to 2014.

In the past decade, several devices were developed in order to target the autonomic nervous system and lower BP in patients with uncontrolled hypertension. These devices aim to provide additional treatment option for patients who do not respond to antihypertensive medication. These devices target other BP regulating mechanisms such as baroreflex activation, deep brain stimulation carotid body ablation, direct vagus nerve stimulation, cardiac neuromodulation, central iliac arteriovenous coupler as well as other devices are currently under research, however, there is no medical device that has been approved so far.

The Therapeutic Intra Vascular UltraSound (TIVUS™) System is designed for renal artery nerve ablation using transluminal ultrasound (US). The TIVUS™ System is a high intensity, non-focused, ultrasound catheter system, which enables remote, localized, controlled, and repeatable thermal modulation of nerves adjacent to arterial vessel wall for performing safe and effective therapeutic artery sympathetic denervation. The ultrasonic energy is transmitted from a catheter positioned within the artery lumen, while avoiding direct contact with the artery wall.

Inclusion Criteria:

1. Written informed consent to participate in the study obtained from the patient, according to local regulations, prior to initiation of any study mandated procedure.
2. Male or female, ≥ 18 years of age and ≤ 80 years of age at the time of screening.
3. Individual has office systolic blood pressure (SBP) ≥ 140 mm Hg but < 180 mm Hg, and a diastolic blood pressure (DBP) ≥ 90 mm Hg but < 110 mm Hg based on an average of 3 office seated blood pressure readings measured by a manual, automated or semi-automated validated BP monitor, on current medications. 4. Documented mean daytime ABPM systolic blood pressure (SBP) ≥ 135 mm Hg but < 180 mm Hg, after a 4 week stabilization period.

5. Patient is either on at least one anti-hypertensive medication at maximal tolerated dose with a medically documented intolerance to one or more medications, or on three medications where one is a diuretic.

6. Patient is willing and expected to maintain their anti-hypertensive medication regimen for at least 3 months.

7. Patient is able and willing to comply with all study procedures.

Exclusion Criteria:

1. Patient has been previously diagnosed with abnormal renal artery anatomy and/or renal anatomy such as single kidney, other renal development anomaly such as ectopic or horseshoe kidney, or polycystic kidney disease precluding renal denervation therapy as detailed in the angiographic exclusion criteria.
2. Pregnant or breastfeeding women or women planning a pregnancy within 12 months of study enrollment.
3. Patient has an estimated glomerular filtration rate (eGFR) of < 40mL/min/1.73m2 CKD-EPI as calculated using the CKD-EPI 2021 equation.
4. Patients with uncontrolled rapid AF.
5. Patient has had a previous renal denervation procedure.
6. Patients with daytime ABPM mean systolic blood pressure (SBP) > 180 mm Hg.
7. Patient has Type 1 diabetes or poorly controlled Type 2 diabetes (HbA1c > 9%).
8. Patients with history of myocardial infarction, unstable angina pectoris, heart failure, cerebrovascular accident, or widespread atherosclerosis, with documented intravascular thrombosis or unstable plaques.
9. Patient has a planned major surgery or cardiovascular intervention in the next 6 months.
10. Patient who has undergone a major surgery or cardiovascular intervention in the previous 3 months.
11. Patient has frequent intermittent or chronic pain that results in treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) for two or more days per week over the month prior to enrollment.
12. Patient is taking immunosuppressive therapy for diseases featuring vasculitis.
13. Patient on anticoagulant therapy that cannot be temporarily withheld for study procedure.
14. Contraindication to recommended denervation procedure medications or intravascular contrast that cannot be adequately controlled with pre-medication.
15. Concurrent enrollment in another device or drug trial that has not completed the primary endpoint or clinically interferes with the current study endpoints. For patient previously participating in a drug trial, allow a wash-off period of at least 5 half-lives of the investigational drug.
16. Patient with significant co-morbid condition(s) which, at the discretion of the PI, are deemed to prohibit study entry.
17. Patient works the night shift.
18. Patient has valvular stenosis with risk of cardiac event with significant and/or abrupt decline in systolic blood pressure.
19. Untreated secondary cause of hypertension.
20. Device therapy within the past five years for the treatment of hypertension.
21. Prior renal stent or angioplasty.
22. Life expectancy <1 year.
23. Patients with history of renal transplant or planned renal transplantation within the next year.
24. History of one or more episodes of severe orthostatic hypotension within the past year.
25. Patient has unstable cardiac or pulmonary disease (including pulmonary hypertension) requiring chronic oxygen support.
26. Uncontrolled or inadequately treated bleeding diathesis.
27. Evidence of active infection within 7 days of procedure

Angiographic Exclusion Criteria

The following characteristics identified either on the renal artery CT scan or on the Eligibility II Renal artery Angiogram will prevent the patient from being included:

1. Main renal arteries < 4 mm in lumen diameter or < 20 mm in length; accessory renal arteries, if present, < 4 mm in lumen diameter or <10 mm in length.
2. Aorto-renal angle that in the operator's opinion prevents a safe cannulation of the renal artery.
3. Severe common femoral artery, common and/or external iliac artery, renal, iliac or aortic calcification or tortuosity that may compromise the safe performance and completion of the TIVUS™ procedure.
4. Hemodynamically or anatomically significant renal artery abnormality or stenosis in either renal artery which, in the operator's opinion, would interfere with safe cannulation of the renal artery or meets local standards for surgical repair or interventional dilation (NOTE: vessel areas with calcification and fibromuscular dysplasia (FMD) should be avoided as intended treatment areas).
5. Any renal artery stenosis > 30% by visual assessment.
6. Any renal artery aneurysm (>50% of the main renal artery reference vessel diameter by visual estimate).
7. Presence of fibromuscular dysplasia
8. Significant renal artery atheroma, aneurysm, calcification in the target vessel identified on CT Angiogram