THRIVE- THerapeutic IntravasculaR Ultrasound (TIVUS™) REnal Denervation System Versus Sham for the Adjunctive Treatment of Hypertension

A Pivotal, Prospective, Multicenter, 2:1 Randomized, Double Blind, Controlled, Study Comparing the THerapeutic IntravasculaR Ultrasound (TIVUS™) REnal Denervation System Versus Sham for the Adjunctive Treatment of Hypertension (The THRIVE Study)

The primary objective of the THRIVE Pivotal study is to demonstrate the adjunctive effectiveness and the safety of the TIVUS system in:

1. subjects with uncontrolled hypertension (HTN) receiving 0 - 2 anti-hypertensive drugs of different classes in whom the anti-hypertensive medications will be stopped for a 4-week wash-out period before RDN/Sham procedure and during 2 months after procedure.
2. subjects with controlled hypertension receiving 1 - 2 anti-hypertensive drugs of different classes and who accept to be off-medications for a 4-week wash-out period before RDN/Sham procedure and 2 months after the procedure

THRIVE is an international, multicenter, randomized, double blind, sham-controlled study, designed to demonstrate the adjunctive effectiveness and safety of the TIVUS System in hypertensive subjects while subjects are maintained off-antihypertensive medications for a 4-week wash-out period before RDN/Sham procedure and 2 months after procedure. At two months after procedure, subjects with uncontrolled hypertension are put back on antihypertensive medication according to a medication escalation protocol. Unblinding will be performed at 6 months. Uncontrolled sham subjects can cross-over to RDN procedure at 6-months. The sham procedure will be minimally invasive to reduce risk to subjects. All subjects treated with TIVUS will be followed for a maximum of 36 months post procedure.

Inclusion Criteria:

1. Appropriately signed and dated informed consent

2. Male and female adults with age between ≥22 and ≤75 years at time of consent

3. Documented history of hypertension

4. Previously or currently prescribed antihypertensive therapy

5. Subject has an office BP (average of 3 seated measurements) of:

   1. Uncontrolled BP: ≥ 140/90 mmHg <180/110 mmHg at Screening Visit (V0) while stable for at least 4 weeks on 0-2 anti-hypertensive medications of different classes* and willing to stop anti-hypertensive medication(s) for 4 weeks wash-out and 2-months post-procedure, (subjects with a history of treatment with anti-hypertensive medications but are not currently taking any at screening will undergo a 4-week run-in period) or,
   2. Controlled BP: < 140/90 mmHg while stable for at least 4 weeks on 1-2 antihypertensive medications of different classes and willing to stop anti-hypertensive medication(s) for 4 weeks wash-out and 2-months post-procedure

6. Able and willing to comply with all study procedures

7. Subject is willing to have and is a good candidate for conscious sedation

Subjects who meet the following criteria will be considered eligible for randomization:

• Documented daytime systolic ABP ≥ 135 mmHg and < 180 mmHg after 4-week washout/run-in period.**

• Suitable renal anatomy compatible with the renal denervation procedure, documented by renal CTA or MRA of good quality performed within one year prior to consent (a CTA or MRA will be obtained in subjects without a recent (≤1 year) cross-sectional renal imaging). The renal angiogram procedure done in the cath lab prior to randomization will serve as the final anatomy compatibility check.

  • Potassium-sparing diuretics such as Amiloride hydrochloride and Triamterene may be prescribed in combination with another diuretic (e.g. a thiazide or loop diuretic) for their potassium conservation properties. In this situation, the diuretic combination is considered as a single class of anti-hypertensive.

Exclusion Criteria:

1. Subject has been previously diagnosed with abnormal renal artery anatomy and/or renal anatomy such as a single kidney, ectopic or horseshoe kidney, polycystic kidney disease, kidney tumors or other findings precluding renal denervation therapy as detailed in the angiographic exclusion criteria

2. Uncorrected causes of secondary hypertension other than sleep apnea (including, but not limited to): aldosteronism, renal parenchymal disease, renovascular disease, excess catecholamines, Cushing's syndrome, erythropoietin use, pheochromocytoma, hypo/hyperthyroidism, hyperparathyroidism, acromegaly)

3. Type I diabetes mellitus or uncontrolled Type II diabetes (defined as a plasma HbA1c ≥ 9.0%)

4. eGFR of <40 mL/min/1.73 m2 CKD-EPI as calculated using the CKD-EPI 2021 equation

5. Cerebrovascular event (e.g. stroke, transient ischemic event, cerebrovascular accident) within 6 months prior to consent

6. History of severe cardiovascular event (e.g. myocardial infarction, unstable angina, CABG, acute heart failure requiring hospitalization (NYHA III-IV) within 12 months prior to consent

7. Subject has severe valvular stenosis or insufficiency

8. Documented repeat (>1) hospitalization for hypertensive crisis within the prior 12 months and/or any hospitalization for hypertensive crisis within three (3) months prior to consent

9. Prescribed to any standard antihypertensive cardiovascular medication (e.g. beta blockers) for other chronic conditions (e.g. ischemic heart disease) such that discontinuation might pose serious risk to health in the opinion of the investigator

10. Subject with rapid, uncontrolled, symptomatic atrial fibrillation

11. Active implantable medical device (e.g. ICD or CRT-D; neuromodulator/spinal stimulator; baroreflex stimulator)

12. Chronic oxygen support or mechanical ventilation other than nocturnal respiratory support for sleep apnea.

13. Subject has a planned major surgery (any procedure requiring general anesthesia) in the next 12 months.

14. Subject on anticoagulant therapy that cannot be temporarily withheld for study procedure.

15. Primary pulmonary hypertension

16. Documented contraindication or allergy to contrast medium not amenable to treatment

17. Limited life expectancy of < 1 year at the discretion of the Investigator

18. Night shift worker

19. Subject 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.

20. Subject is taking immunosuppressive therapy for diseases featuring vasculitis

21. Any known, unresolved history of drug use or alcohol dependency, lacks the ability to comprehend or follow instructions, or for any reason in the opinion of the investigator, would be unlikely or unable to comply with study protocol requirements or whose participation may result in data analysis confounders

22. Pregnant, nursing or planning to become pregnant within 12 months post procedure.

    Negative pregnancy test required, documented within a maximum of 7 days prior to procedure for all women of childbearing potential. Documentation of effective contraception is also required for women of childbearing potential

23. Subject has a planned major surgery or cardiovascular intervention in the next 6 months

24. Subject with history of renal transplantation

25. Evidence of active infection within 7 days of procedure (based on positive lab test and requiring therapy).

26. Subject has hypertrophic cardiomyopathy or amyloidosis.

27. Prior renal denervation procedure

28. Concurrent enrollment in any other investigational drug or device trial (participation in non-interventional studies/registries is acceptable)

29. Subject on a beta blocker for a condition other than antihypertension

Angiographic Exclusion Criteria:

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

1. Main renal arteries lumen diameter < 4 mm.
2. Main renal treatable artery length <20mm (may include proximal branching).
3. Accessory renal arteries that supplies ≥ 25% of the parenchyma, and < 4 mm in lumen diameter.
4. Aorto-renal angle that prevents a safe cannulation of the renal artery.
5. 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.
6. Hemodynamically or anatomically significant renal artery abnormality or stenosis in either renal artery which, 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).
7. Any renal artery stenosis > 30% by visual assessment.
8. Any renal artery aneurysm (>50% of the main renal artery reference vessel diameter by visual estimate).
9. Presence of fibromuscular dysplasia of the renal arteries
10. Significant renal artery atheroma, aneurysm, calcification in the target vessel identified on CT Angiogram